Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases

ABSTRACT

Provided herein are methods of treating or ameliorating a pediatric cholestatic liver disease by non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Also provided are methods for treating or ameliorating a pediatric liver disease, decreasing the levels of serum bile acids or hepatic bile acids, treating or ameliorating pruritis, reducing liver enzymes, or reducing bilirubin comprising non-systemically administering to an individual in need thereof a therapeutically effective amount of a pediatric formulation comprising an ASBTI or a pharmaceutically acceptable salt thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 13/866,906,filed Apr. 19, 2013, which is a continuation of application Ser. No.13/662,387, filed Oct. 26, 2012, which claims the benefit under 35U.S.C. § 119(e) of U.S. Provisional Application No. 61/553,094, filedOct. 28, 2011, U.S. Provisional Application No. 61/607,487, filed Mar.6, 2012, and U.S. Provisional Application No. 61/607,503, filed Mar. 6,2012, which are incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

Pediatric cholestatic liver diseases affect a small percentage ofchildren, but therapy results in significant healthcare costs each year.Currently, many of the pediatric cholestatic liver diseases requireinvasive and costly treatments such as liver transplantation andsurgery. An effective and less invasive treatment that is suitable forthe pediatric population is not available.

It is well understood and accepted that the therapeutic needs ofchildren are sufficiently different than those of adults as to requirespecific studies of medications in children. For example, oraladministration of a solid dosage form of medication is painless andsimple for most adult patients, but for the pediatric patientpopulation, swallowing an oral solid dosage form produced for adults canbe problematic. In addition, the drugs used in solid dosages often havean unpleasant taste. More importantly, oral administration of adultmedication targeting cholestatic liver diseases may result in sideeffects such as diarrhea and intestinal discomfort. Such problems pose asafety risk and affect compliance. Effective and acceptable forms ofpediatric medication for pediatric cholestastatic liver diseases areneeded.

SUMMARY OF THE INVENTION

Provided herein are therapeutic compositions and methods for treating orameliorating a pediatric cholestatic liver disease or pediatriccholestasis. In certain embodiments, provided herein are methods fortreating or ameliorating a pediatric cholestatic liver diseasecomprising non-systemically administering to a pediatric patient atherapeutically effective amount of a composition comprising an ApicalSodium-dependent Bile Transporter Inhibitor (ASBTI) or apharmaceutically acceptable salt thereof. In certain embodiments,provided herein are methods for treating or ameliorating a pediatriccholestatic liver disease comprising administering to an individual inneed thereof a therapeutically effective amount of a compositioncomprising a non-systemically absorbed ASBTI or a pharmaceuticallyacceptable salt thereof. In certain embodiments, provided herein aremethods for treating or ameliorating a pediatric cholestatic liverdisease comprising non-systemically administering to a pediatric patienta therapeutically effective amount of a pediatric dosage form comprisingan Apical Sodium-dependent Bile Transporter Inhibitor (ASBTI) or apharmaceutically acceptable salt thereof. In certain embodiments,provided herein are methods for treating or ameliorating a pediatriccholestatic liver disease comprising administering to an individual inneed thereof a therapeutically effective amount of a pediatric dosageform comprising a non-systemically absorbed ASBTI or a pharmaceuticallyacceptable salt thereof.

In certain embodiments, provided herein are pediatric dosage formscomprising a pediatric dosage of a non-systemically absorbed ApicalSodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or apharmaceutically acceptable salt thereof. In some embodiments, providedherein are pediatric dosage forms comprising any non-systemicallyabsorbed ASBTI or a pharmaceutically acceptable salt thereof describedherein. In some embodiments, provided herein are pediatric dosage formscomprising any non-systemically absorbed ASBTI or a pharmaceuticallyacceptable salt thereof and a second agent described herein.

Provided herein are therapeutic compositions and methods for treating orameliorating pruritis. In certain embodiments, provided herein aremethods for treating or ameliorating pruritis comprisingnon-systemically administering to a pediatric patient suffering from apediatric cholestatic liver disease a therapeutically effective amountof a composition comprising an ASBTI or a pharmaceutically acceptablesalt thereof. In certain embodiments, provided herein are methods fortreating or ameliorating pruritis comprising administering to anindividual in need thereof a therapeutically effective amount of acomposition comprising a non-systemically absorbed ASBTI or apharmaceutically acceptable salt thereof. In certain embodiments,provided herein are methods for treating or ameliorating pruritiscomprising non-systemically administering to a pediatric patientsuffering from a pediatric cholestatic liver disease a therapeuticallyeffective amount of a pediatric dosage form comprising an ASBTI or apharmaceutically acceptable salt thereof. In certain embodiments,provided herein are methods for treating or ameliorating pruritiscomprising administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form comprising anon-systemically absorbed ASBTI or a pharmaceutically acceptable saltthereof.

Provided herein are therapeutic compositions and methods for treating orameliorating pediatric hypercholemia. In certain embodiments, providedherein are methods for treating or ameliorating pediatric hypercholemiacomprising non-systemically administering to a pediatric patient atherapeutically effective amount of a composition comprising an ASBTI ora pharmaceutically acceptable salt thereof. In certain embodiments,provided herein are methods for treating or ameliorating pediatrichypercholemia comprising administering to an individual in need thereofa therapeutically effective amount of a composition comprising anon-systemically absorbed ASBTI or a pharmaceutically acceptable saltthereof. In certain embodiments, provided herein are methods fortreating or ameliorating pediatric hypercholemia comprisingnon-systemically administering to a pediatric patient a therapeuticallyeffective amount of a pediatric dosage form comprising an ASBTI or apharmaceutically acceptable salt thereof. In certain embodiments,provided herein are methods for treating or ameliorating pediatrichypercholemia comprising administering to an individual in need thereofa therapeutically effective amount of a pediatric dosage form comprisinga non-systemically absorbed ASBTI or a pharmaceutically acceptable saltthereof.

Provided herein are therapeutic compositions and methods for loweringserum bile acid concentrations or hepatic bile acid concentrations. Incertain embodiments, provided herein are methods for decreasing serumbile acid levels or concentrations or hepatic bile acid levels orconcentrations comprising non-systemically administering to a pediatricpatient suffering from a pediatric cholestatic liver disease atherapeutically effective amount of a composition comprising an ASBTI ora pharmaceutically acceptable salt thereof. In certain embodiments,provided herein are methods for decreasing serum bile acids or hepaticbile acids comprising administering to an individual in need thereof atherapeutically effective amount of a composition comprising anon-systemically absorbed ASBTI or a pharmaceutically acceptable saltthereof. In certain embodiments, provided herein are methods fordecreasing serum bile acid levels or concentrations or hepatic bile acidlevels or concentrations comprising non-systemically administering to apediatric patient suffering from a pediatric cholestatic liver disease atherapeutically effective amount of a pediatric dosage form comprisingan ASBTI or a pharmaceutically acceptable salt thereof. In certainembodiments, provided herein are methods for decreasing serum bile acidsor hepatic bile acids comprising administering to an individual in needthereof a therapeutically effective amount of a pediatric dosage formcomprising a non-systemically absorbed ASBTI or a pharmaceuticallyacceptable salt thereof.

In some embodiments, compositions and methods provided herein decreaseserum or hepatic bile acid levels by at least 50%, 45%, 40%, 35%, 30%,25%, 20%, 15%, or 10%, as compared to the levels prior to administrationof the compositions provided herein or as compared to control subjects.In some embodiments, methods provided herein decrease serum or hepaticbile acid levels by at least 30%. In some embodiments, methods providedherein decrease serum or hepatic bile acid levels by at least 25%. Insome embodiments, methods provided herein decrease serum or hepatic bileacid levels by at least 20%. In some embodiments, methods providedherein decrease serum or hepatic bile acid levels by at least 15%.

Provided herein are therapeutic compositions and methods for treating orameliorating xanthoma. In certain embodiments, provided herein aremethods for treating or ameliorating xanthoma comprisingnon-systemically administering to a pediatric patient suffering from apediatric cholestatic liver disease a therapeutically effective amountof a composition comprising an ASBTI or a pharmaceutically acceptablesalt thereof. In certain embodiments, provided herein are methods fortreating or ameliorating xanthoma comprising administering to anindividual in need thereof a therapeutically effective amount of acomposition comprising a non-systemically absorbed ASBTI or apharmaceutically acceptable salt thereof. In certain embodiments,provided herein are methods for treating or ameliorating xanthomacomprising non-systemically administering to a pediatric patientsuffering from a pediatric cholestatic liver disease a therapeuticallyeffective amount of a pediatric dosage form comprising an ASBTI or apharmaceutically acceptable salt thereof. In certain embodiments,provided herein are methods for treating or ameliorating xanthomacomprising administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form comprising anon-systemically absorbed ASBTI or a pharmaceutically acceptable saltthereof.

In some embodiments, provided herein are compositions and methodsdecreasing serum lipoprotein X levels or concentrations comprisingnon-systemically administering to a pediatric patient suffering fromxanthoma a therapeutically effective amount of a composition comprisingan ASBTI or a pharmaceutically acceptable salt thereof. In certainembodiments, provided herein are methods for decreasing serumlipoprotein X comprising administering to an individual in need thereofa therapeutically effective amount of a composition comprising anon-systemically absorbed ASBTI or a pharmaceutically acceptable saltthereof. In certain embodiments, provided herein are methods fordecreasing serum lipoprotein X levels or concentrations comprisingnon-systemically administering to a pediatric patient suffering fromxanthoma a therapeutically effective amount of a pediatric dosage formcomprising an ASBTI or a pharmaceutically acceptable salt thereof. Incertain embodiments, provided herein are methods for decreasing serumlipoprotein X comprising administering to an individual in need thereofa therapeutically effective amount of a pediatric dosage form comprisinga non-systemically absorbed ASBTI or a pharmaceutically acceptable saltthereof.

In certain embodiments, described herein are compositions and methodsfor reducing serum levels of bilirubin, gamma-glutamyl transpeptidase orgamma-glutamyl transferase (GGT), or liver enzymes, such as alkalinephosphatase, ALT and AST, in an individual in need thereof comprisingnon-systemically administering a therapeutically effective amount of acomposition of an ASBTI or a pharmaceutically acceptable salt thereof.In some embodiments, methods comprise administering a therapeuticallyeffective amount of a composition comprising a non-systemically absorbedASBTI or a pharmaceutically acceptable salt thereof. In certainembodiments, described herein are methods for reducing serum levels ofbilirubin, gamma-glutamyl transpeptidase or gamma-glutamyl transferase(GGT), or liver enzymes, such as alkaline phosphatase, ALT and AST, inan individual in need thereof comprising non-systemically administeringa therapeutically effective amount of a pediatric dosage form of anASBTI or a pharmaceutically acceptable salt thereof. In someembodiments, methods comprise administering a therapeutically effectiveamount of a pediatric dosage form comprising a non-systemically absorbedASBTI or a pharmaceutically acceptable salt thereof.

In certain embodiments, methods provided herein comprise administeringcompounds that inhibit the ASBT or any recuperative bile salttransporter. In certain embodiments, use of the compounds providedherein reduces or inhibits recycling of bile acid salts in thegastrointestinal tract. In some embodiments, the methods provided hereinreduce intraenterocyte bile acids/salts or reduce necrosis and/or damageto intestinal or hepatocellular architecture.

In certain embodiments, the methods described herein treat or amelioratea pediatric cholestatic liver disease by increasing intraluminalconcentrations of bile acids/salts, which are then excreted in thefeces, thereby reducing overall bile acid and serum bile acid or hepaticbile acid load in an individual in need thereof. In certain embodiments,increasing intraluminal bile acid concentrations according to methodsdescribed herein provide protection and/or control of the integrity ofan individual's liver and/or intestine that has been injured bycholestasis and/or cholestatic liver disease.

In certain embodiments, the methods described herein treat or amelioratepruritis by increasing intraluminal concentrations, and/or reducingserum concentrations, or hepatic concentrations of bile acids/salts inan individual in need thereof. In certain embodiments, increasingintraluminal bile acid concentrations according to methods describedherein provide protection and/or control of the integrity of anindividual's liver and/or intestine that has been injured by acholestatic liver disease.

In certain embodiments, the methods described herein lower serum bileacid concentrations or hepatic bile acid concentrations by increasingintraluminal concentrations of bile acids/salts in an individual in needthereof. In certain embodiments, increasing intraluminal bile acidconcentrations according to methods described herein provide protectionand/or control of the integrity of an individual's liver and/orintestine that has been injured by a cholestatic liver disease.

In certain embodiments, provided herein is an ASBTI or apharmaceutically acceptable salt thereof for use in the treatment of apediatric cholestatic liver disease, wherein the ASBTI isnon-systemically absorbed or is formulated to be non-systemicallyabsorbed. In some embodiments, provided herein is a pharmaceuticalcomposition for use in the treatment of a pediatric cholestatic liverdisease, wherein the composition comprises a pediatric dosage form of anASBTI and a pharmaceutically acceptable excipient, wherein the ASBTI isnon-systemically absorbed or is formulated to be non-systemicallyabsorbed. In some embodiments, a composition provided herein is suitablefor non-systemically administering to the distal ileum, colon, and/orrectum.

In certain embodiments, provided herein is an ASBTI or apharmaceutically acceptable salt thereof for use in the treatment ofpruritis in a pediatric patient suffering from a pediatric cholestaticliver disease, wherein the ASBTI is non-systemically absorbed or isformulated to be non-systemically absorbed. In some embodiments,provided herein is a pharmaceutical composition for use in the treatmentof pruritis, wherein the composition comprises a pediatric dosage formof an ASBTI and a pharmaceutically acceptable excipient, wherein theASBTI is non-systemically absorbed or is formulated to benon-systemically absorbed. In some embodiments, a composition providedherein is suitable for non-systemically administering to the distalileum, colon, and/or rectum.

In certain embodiments, provided herein is an ASBTI or apharmaceutically acceptable salt thereof for use in lowering serum bileacid concentrations or hepatic bile acid concentrations in a pediatricpatient suffering from a pediatric cholestatic liver disease, whereinthe ASBTI is a non-systemically absorbed or is formulated to benon-systemically absorbed. In some embodiments, provided herein is apharmaceutical composition for use in lowering serum bile acidconcentrations or hepatic bile acid concentrations, wherein thecomposition comprises a pediatric dosage form of an ASBTI and apharmaceutically acceptable excipient, wherein the ASBTI isnon-systemically absorbed or is formulated to be non-systemicallyabsorbed. In some embodiments, a composition provided herein is suitablefor non-systemically administering to the distal ileum, colon, and/orrectum.

In some embodiments, an ASBTI provided herein is minimally absorbed orformulated to be minimally absorbed. In some embodiments, a pediatricdosage form of an ASBTI is non-systemically administered to the distalileum, colon, and/or rectum of an individual in need thereof. In someembodiments, an ASBTI is non-systemically administered to the ileum,colon or rectum of an individual in need thereof. In some embodiments,less than 50%, less than 40%, less than 30%, less than 20%, less than10%, less than 9%, less than 8%, less than 7%, less than 6%, less than5%, less than 4%, less than 3%, less than 2%, or less than 1% of theASBTI is systemically absorbed. In a preferred embodiment, less than 10%of the ASBTI is systemically absorbed. In another preferred embodiment,less than 5% of the ASBTI is systemically absorbed. In another preferredembodiment, less than 1% of the ASBTI is systemically absorbed.

In one aspect, provided herein is a method for treating a pediatriccholestatic liver disease in an individual in need thereof comprisingnon-systemically administering to the distal gastrointestinal tract ofthe individual in need thereof a therapeutically effective amount of apediatric dosage form of an ASBTI or a pharmaceutically acceptable saltthereof. In one aspect, provided herein is a method for treatingpruritis in an individual in need thereof comprising non-systemicallyadministering to the distal gastrointestinal tract of the individual inneed thereof a therapeutically effective amount of a pediatric dosageform of an ASBTI or a pharmaceutically acceptable salt thereof. In oneaspect, provided herein is a method for lowering serum bile acidconcentrations in an individual in need thereof comprisingnon-systemically administering to the distal gastrointestinal tract ofthe individual in need thereof a therapeutically effective amount of apediatric dosage form of an ASBTI or a pharmaceutically acceptable saltthereof. In some embodiments, the distal gastrointestinal tract isjejunum, ileum, colon, or rectum. In some embodiments, the distalgastrointestinal tract is ileum, colon, or the rectum. In someembodiments, the distal gastrointestinal tract is jejunum. In someembodiments, the distal gastrointestinal tract is ileum.

In certain embodiments, the pediatric cholestatic liver disease isprogressive familial intrahepatic cholestasis (PFIC), PFIC type 1, PFICtype 2, PFIC type 3, Alagille syndrome, Dubin-Johnson Syndrome, biliaryatresia, post-Kasai biliary atresia, post-liver transplantation biliaryatresia, post-liver transplantation cholestasis, post-livertransplantation associated liver disease, intestinal failure associatedliver disease, bile acid mediated liver injury, pediatric primarysclerosing cholangitis, MRP2 deficiency syndrome, neonatal sclerosingcholangitis, a pediatric obstructive cholestasis, a pediatricnon-obstructive cholestasis, a pediatric extrahepatic cholestasis, apediatric intrahepatic cholestasis, a pediatric primary intrahepaticcholestasis, a pediatric secondary intrahepatic cholestasis, benignrecurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2,BRIC type 3, total parenteral nutrition associated cholestasis,paraneoplastic cholestasis, Stauffer syndrome, drug-associatedcholestasis, infection-associated cholestasis, or gallstone disease. Insome embodiments, the pediatric cholestatic liver disease is a pediatricform of liver disease described herein.

In certain embodiments, a pediatric cholestatic liver disease ischaracterized by one or more symptoms selected from jaundice, pruritis,cirrhosis, hypercholemia, neonatal respiratory distress syndrome, lungpneumonia, increased serum concentration of bile acids, increasedhepatic concentration of bile acids, increased serum concentration ofbilirubin, hepatocellular injury, liver scarring, liver failure,hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea,pancreatitis, hepatocellular necrosis, giant cell formation,hepatocellular carcinoma, gastrointestinal bleeding, portalhypertension, hearing loss, fatigue, loss of appetite, anorexia,peculiar smell, dark urine, light stools, steatorrhea, failure tothrive, and/or renal failure.

In certain embodiments, the pediatric patient is a new born, a pre-termnew born, an infant, a toddler, a pre-schooler, a school-age child, apre-pubescent child, post-pubescent child, an adolescent, or a teenagerunder the age of eighteen. In some embodiments, the pediatric patient isa new born, a pre-term new born, an infant, a toddler, a pre-schooler,or a school-age child. In some embodiments, the pediatric patient is anew born, a pre-term new born, an infant, a toddler, or a pre-schooler.In some embodiments, the pediatric patient is a new born, a pre-term newborn, an infant, or a toddler. In some embodiments, the pediatricpatient is a new born, a pre-term new born, or an infant. In someembodiments, the pediatric patient is a new born. In some embodiments,the pediatric patient is an infant. In some embodiments, the pediatricpatient is a toddler.

In certain embodiments, the individual is an infant less than 2 years ofage. In some cases, for any of the methods and/or compositions describedherein, the individual is an infant between 0 to 18 months of age. Insome cases, for any of the methods and/or compositions described herein,the individual is an infant between 1 to 18 months of age. In somecases, for any of the methods and/or compositions described herein, theindividual is an infant between 2 to 18 months of age. In some cases,for any of the methods and/or compositions described herein, theindividual is an infant between 3 to 18 months of age. In some cases,for any of the methods and/or compositions described herein, theindividual is an infant between 4 to 18 months of age. In some cases,for any of the methods and/or compositions described herein, theindividual is an infant between 6 to 18 months of age. In some cases,for any of the methods and/or compositions described herein, theindividual is an infant between 18 to 24 months of age. In some cases,for any of the methods and/or compositions described herein, theindividual is an infant between 6 to 12 months of age. In someinstances, for any of the methods and/or compositions described herein,the individual is a child of between about 2 to about 10 years of age.In some instances, the individual is less than about 10 years old. Insome instances, the individual is between about 10 to about 17 yearsold.

In some cases, for any of the methods and/or compositions describedherein, the individual is a child between 6 months to 12 years of age.

Provided herein, in certain embodiments, are therapeutic methods andcompositions using compounds that inhibit the Apical Sodium-dependentBile Transporter (ASBT) or a pharmaceutically acceptable salt thereof,or any recuperative bile salt transporter for treatment of a pediatriccholestatic liver disease or pruritis or for lowering serum bile acidconcentrations. In certain instances, use of the compounds providedherein reduces or inhibits recycling of bile acid salts in thegastrointestinal tract. In some embodiments, the methods provided hereinreduce intraenterocyte bile acids/salts and/or damage to ileal orhepatocellular architecture caused by a pediatric cholestatic liverdisease and/or allow for regeneration of the intestinal lining or liver.In some embodiments, the bile transport inhibitors are non-systemiccompounds. In other embodiments, the bile acid transporter inhibitorsare systemic compounds delivered non-systemically. In other embodiments,the bile acid transporter inhibitors are systemic compounds. In certainembodiments, the bile transport inhibitors described herein enhanceenteroendocrine peptide secretion by intestinal L-cells.

In some embodiments of the methods described above, the ASBTI is acompound of Formula I or a pharmaceutically acceptable salt thereof, asdescribed herein. In some embodiments of the methods described above,the ASBTI is a compound of Formula II or a pharmaceutically acceptablesalt thereof, as described herein. In some embodiments of the methodsdescribed above, the ASBTI is a compound of Formula III or apharmaceutically acceptable salt thereof, as described herein. In someembodiments of the methods described above, the ASBTI is a compound ofFormula IV or a pharmaceutically acceptable salt thereof, as describedherein. In some embodiments of the methods described above, the ASBTI isa compound of Formula V or a pharmaceutically acceptable salt thereof,as described herein. In some embodiments of the methods described above,the ASBTI is a compound of Formula VI or Formula VID or apharmaceutically acceptable salt thereof, as described herein.

In some embodiments, provided herein is a method for treating orameliorating a pediatric cholestatic liver disease comprisingnon-systemically administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula I or a pharmaceutically acceptable salt thereof. In someembodiments, provided herein is a method for treating or amelioratingpruritis comprising non-systemically administering to an individual inneed thereof a therapeutically effective amount of a pediatric dosageform of an ASBTI of Formula I or a pharmaceutically acceptable saltthereof. In some embodiments, provided herein is a method for increasingthe levels of an enteroendocrine peptide or hormone in an individualsuffering from a pediatric cholestatic liver disease comprisingnon-systemically administering to the individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula I or a pharmaceutically acceptable salt thereof. In someembodiments, provided herein is a method for lowering serum bile acidconcentrations or hepatic bile acid concentration comprisingnon-systemically administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula I or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a method for treating orameliorating a pediatric cholestatic liver disease comprisingnon-systemically administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula II or a pharmaceutically acceptable salt thereof. In someembodiments, provided herein is a method for treating or amelioratingpruritis comprising non-systemically administering to an individual inneed thereof a therapeutically effective amount of a pediatric dosageform of an ASBTI of Formula II or a pharmaceutically acceptable saltthereof. In some embodiments, provided herein is a method for increasingthe levels of an enteroendocrine peptide or hormone in an individualsuffering from a pediatric cholestatic liver disease comprisingnon-systemically administering to the individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula II or a pharmaceutically acceptable salt thereof. In someembodiments, provided herein is a method for lowering serum bile acidconcentrations or hepatic bile acid concentration comprisingnon-systemically administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula II or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a method for treating orameliorating a pediatric cholestatic liver disease comprisingnon-systemically administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula III or a pharmaceutically acceptable salt thereof. In someembodiments, provided herein is a method for treating or amelioratingpruritis comprising non-systemically administering to an individual inneed thereof a therapeutically effective amount of a pediatric dosageform of an ASBTI of Formula III or a pharmaceutically acceptable saltthereof. In some embodiments, provided herein is a method for increasingthe levels of an enteroendocrine peptide or hormone in an individualsuffering from a pediatric cholestatic liver disease comprisingnon-systemically administering to the individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula III or a pharmaceutically acceptable salt thereof. In someembodiments, provided herein is a method for lowering serum bile acidconcentrations or hepatic bile acid concentration comprisingnon-systemically administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula III or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a method for treating orameliorating a pediatric cholestatic liver disease comprisingnon-systemically administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula IV or a pharmaceutically acceptable salt thereof. In someembodiments, provided herein is a method for treating or amelioratingpruritis comprising non-systemically administering to an individual inneed thereof a therapeutically effective amount of a pediatric dosageform of an ASBTI of Formula IV or a pharmaceutically acceptable saltthereof. In some embodiments, provided herein is a method for increasingthe levels of an enteroendocrine peptide or hormone in an individualsuffering from a pediatric cholestatic liver disease comprisingnon-systemically administering to the individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula IV or a pharmaceutically acceptable salt thereof. In someembodiments, provided herein is a method for lowering serum bile acidconcentrations or hepatic bile acid concentration comprisingnon-systemically administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula IV or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a method for treating orameliorating a pediatric cholestatic liver disease comprisingnon-systemically administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula V or a pharmaceutically acceptable salt thereof. In someembodiments, provided herein is a method for treating or amelioratingpruritis comprising non-systemically administering to an individual inneed thereof a therapeutically effective amount of a pediatric dosageform of an ASBTI of Formula V or a pharmaceutically acceptable saltthereof. In some embodiments, provided herein is a method for increasingthe levels of an enteroendocrine peptide or hormone in an individualsuffering from a pediatric cholestatic liver disease comprisingnon-systemically administering to the individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula V or a pharmaceutically acceptable salt thereof. In someembodiments, provided herein is a method for lowering serum bile acidconcentrations or hepatic bile acid concentration comprisingnon-systemically administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula V or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a method for treating orameliorating a pediatric cholestatic liver disease comprisingnon-systemically administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula VI or a pharmaceutically acceptable salt thereof. In someembodiments, provided herein is a method for treating or amelioratingpruritis comprising non-systemically administering to an individual inneed thereof a therapeutically effective amount of a pediatric dosageform of an ASBTI of Formula VI or a pharmaceutically acceptable saltthereof. In some embodiments, provided herein is a method for increasingthe levels of an enteroendocrine peptide or hormone in an individualsuffering from a pediatric cholestatic liver disease comprisingnon-systemically administering to the individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula VI or a pharmaceutically acceptable salt thereof. In someembodiments, provided herein is a method for lowering serum bile acidconcentrations or hepatic bile acid concentration comprisingnon-systemically administering to an individual in need thereof atherapeutically effective amount of a pediatric dosage form of an ASBTIof Formula VI or a pharmaceutically acceptable salt thereof.

In certain embodiments, an ASBTI is any compound described herein thatinhibits recycling of bile acids/salts in the gastrointestinal tract ofan individual. In certain embodiments, an ASBTI is (−)-(3R,5R)-trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine1,1-dioxide; (“Compound 100A”) or any other salt or analog thereof. Incertain of any of the aforementioned embodiments, an ASBTI is1-[4-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]4-aza-1-azoniabicyclo[2.2.2]octanemethane sulfonate salt (“Compound 100B”) or any other salt or analogthereof. In certain embodiments, an ASBTI is N,N-dimethylimido-dicarbonimidic diamide (“Compound 100C”) or any salt oranalog thereof. In certain embodiments, an ASBTI is any commerciallyavailable ASBTI including but not limited to SD-5613, A-3309, 264W94,S-8921, SAR-548304, BARI-1741, HMR-1453, TA-7552, R-146224, or SC-435.In some embodiments, an ASBTI is1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxyethyl)carbamoyl]benzyl)}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—(S)-1-[N—((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—{(R)-α-carboxy4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl}carbamoyl]methyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N′—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl}carbamoyl]methyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N′—((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;or a pharmaceutically acceptable salt thereof;1-[[5-[[3-[(3S,4R,5R)-3-butyl-7-(dimethylamino)-3-ethyl-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5yl]phenyl]amino]-5-oxopentyl]amino]-1-deoxy-D-glucitol;orPotassium((2R,3R,4S,5R,6R)-4-benzyloxy-6-{3-[3-((3S,4R,5R)-3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)-phenyl]-ureido}-3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl)sulphateethanolate, hydrate. In certain embodiments, an ASBTI is 264W94 (Glaxo),SC-435 (Pfizer), SD-5613 (Pfizer), or A3309 (Astra-Zeneca).

In certain embodiments, methods provided herein further compriseadministration of a second agent selected from ursodiol, UDCA,cholestyramine/resins, antihistamine agents (e.g., hydroxyzine,diphenhydamine), rifampin, nalaxone, Phenobarbital, dronabinol (CB 1agonist), methotrexate, corticosteroids, cyclosporine, colchicines,TPGS—vitamin A, D, E, or K optionally with polyethylene glycol, zinc,and a resin or sequestrant for absorbing bile acids or an analogthereof. In certain embodiments, methods provided herein furthercomprise administration of a second agent selected from a bile acid orsalt with reduced toxicity or a hydrophilic bile acid such as ursodiol,norursodiol, ursodeoxycholic acid, chenodeoxycholic acid, cholic acid,taurocholic acid, ursocholic acid, glycocholic acid, glycodeoxycholicacid, taurodeoxycholic acid, taurocholate, glycochenodeoxycholic acid,or tauroursodeoxycholic acid.

In certain embodiments, provided herein are pediatric dosage forms suchas a solution, syrup, suspension, elixir, powder for reconstitution assuspension or solution, dispersible/effervescent tablet, chewabletablet, gummy candy, lollipop, freezer pops, troches, oral thin strips,orally disintegrating tablet, sachet, soft gelatin capsule, and sprinkleoral powder or granules.

In some embodiments, the pediatric dosage of an ASBTI is between about 1μg/kg/day and about 10 mg/kg/day. In some embodiments, the pediatricdosage of an ASBTI is between about 5 μg/kg/day and about 1 mg/kg/day.In some embodiments, the pediatric dosage of an ASBTI is between about10 μg/kg/day and about 300 μg/kg/day. In some embodiments, the pediatricdosage of an ASBTI is any dosage from about 14 μg/kg/day and about 280μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is anydosage from about 14 μg/kg/day and about 140 μg/kg/day. In someembodiments, the pediatric dosage of an ASBTI is between about 5μg/kg/day and about 200 μg/kg/day. In some embodiments, the pediatricdosage of an ASBTI is between about 10 μg/kg/day and about 200μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI isbetween about 10 pig/kg/day and about 175 μg/kg/day. In someembodiments, the pediatric dosage of an ASBTI is between about 10μg/kg/day and about 150 μg/kg/day. In some embodiments, the pediatricdosage of an ASBTI is between about 10 μg/kg/day and about 140μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI isbetween about 25 μg/kg/day and about 140 μg/kg/day. In some embodiments,the pediatric dosage of an ASBTI is between about 50 μg/kg/day and about140 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI isbetween about 70 μg/kg/day and about 140 μg/kg/day. In some embodiments,the pediatric dosage of an ASBTI is between about 10 μg/kg/day and about100 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is10 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is20 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is30 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is35 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is40 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is50 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is60 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is70 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is80 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is90 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is100 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is110 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is120 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is130 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is140 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is150 μg/kg/day. In some embodiments, the pediatric dosage of an ASBTI is175 μg/kg/day.

In some embodiments, provided herein are pediatric dosages of an ASBTIbetween 14 μg/kg/day and 140 μg/kg/day, or between 14 μg/kg/day and 280μg/kg/day.

In some embodiments, the pediatric dosage of an ASBTI is between about0.5 mg/day and about 40 mg/day. In some embodiments, the pediatricdosage of an ASBTI is between about 0.5 mg/day and about 30 mg/day. Insome embodiments, the pediatric dosage of an ASBTI is between about 1mg/day and about 20 mg/day. In some embodiments, the pediatric dosage ofan ASBTI is between about 1 mg/day and about 10 mg/day. In someembodiments, the pediatric dosage of an ASBTI is between about 1 mg/dayand about 5 mg/day. In some embodiments, the pediatric dosage of anASBTI is 1 mg/day. In some embodiments, the pediatric dosage of an ASBTIis 5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 10mg/day. In some embodiments, the pediatric dosage of an ASBTI is 20mg/day. In some embodiments, the pediatric dosage of an ASBTI is between0.5 mg/day and 5 mg/day. In some embodiments, the pediatric dosage of anASBTI is between 0.5 mg/day and 4.5 mg/day. In some embodiments, thepediatric dosage of an ASBTI is between 0.5 mg/day and 4 mg/day. In someembodiments, the pediatric dosage of an ASBTI is between 0.5 mg/day and3.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI isbetween 0.5 mg/day and 3 mg/day. In some embodiments, the pediatricdosage of an ASBTI is between 0.5 mg/day and 2.5 mg/day. In someembodiments, the pediatric dosage of an ASBTI is between 0.5 mg/day and2 mg/day. In some embodiments, the pediatric dosage of an ASBTI isbetween 0.5 mg/day and 1.5 mg/day. In some embodiments, the pediatricdosage of an ASBTI is between 0.5 mg/day and 1 mg/day. In someembodiments, the pediatric dosage of an ASBTI is between 1 mg/day and4.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI isbetween 1 mg/day and 4 mg/day. In some embodiments, the pediatric dosageof an ASBTI is between 1 mg/day and 3.5 mg/day. In some embodiments, thepediatric dosage of an ASBTI is between 1 mg/day and 3 mg/day. In someembodiments, the pediatric dosage of an ASBTI is between 1 mg/day and2.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI isbetween 1 mg/day and 2 mg/day. In some embodiments, the pediatric dosageof an ASBTI is 0.5 mg/day. In some embodiments, the pediatric dosage ofan ASBTI is 1 mg/day. In some embodiments, the pediatric dosage of anASBTI is 1.5 mg/day. In some embodiments, the pediatric dosage of anASBTI is 2 mg/day. In some embodiments, the pediatric dosage of an ASBTIis 2.5 mg/day. In some embodiments, the pediatric dosage of an ASBTI is3 mg/day. In some embodiments, the pediatric dosage of an ASBTI is 3.5mg/day. In some embodiments, the pediatric dosage of an ASBTI is 4mg/day. In some embodiments, the pediatric dosage of an ASBTI is 4.5mg/day. In some embodiments, the pediatric dosage of an ASBTI is 5mg/day. In some embodiments, the pediatric dosage described herein isthe dosage of the total composition administered.

In some embodiments, the pediatric dosage form comprises 0.5 mg of theASBTI. In some embodiments, the pediatric dosage form comprises 1 mg ofthe ASBTI. In some embodiments, the pediatric dosage form comprises 2.5mg of the ASBTI. In some embodiments, the pediatric dosage formcomprises 5 mg of the ASBTI. In some embodiments, the pediatric dosageform comprises 10 mg of the ASBTI. In some embodiments, the pediatricdosage form comprises 20 mg of the ASBTI.

In certain embodiments, the pediatric dosage of an ASBTI is given once aday. In some embodiments, the pediatric dosage of an ASBTI is given q.d.In some embodiments, the pediatric dosage of an ASBTI is given once aday in the morning. In some embodiments, the pediatric dosage of anASBTI is given once a day at noon. In some embodiments, the pediatricdosage of an ASBTI is given once a day in the evening or night. In someembodiments, the pediatric dosage of an ASBTI is given twice a day. Insome embodiments, the pediatric dosage of an ASBTI is given b.i.d. Insome embodiments, the pediatric dosage of an ASBTI is given twice a day,in the morning and noon. In some embodiments, the pediatric dosage of anASBTI is given twice a day, in the morning and evening. In someembodiments, the pediatric dosage of an ASBTI is given twice a day, inthe morning and night. In some embodiments, the pediatric dosage of anASBTI is given twice a day, at noon and in the evening. In someembodiments, the pediatric dosage of an ASBTI is given twice a day, atnoon and in the night. In some embodiments, the pediatric dosage of anASBTI is given three times a day. In some embodiments, the pediatricdosage of an ASBTI is given t.i.d. In some embodiments, the pediatricdosage of an ASBTI is given four times a day. In some embodiments, thepediatric dosage of an ASBTI is given q.i.d. In some embodiments, thepediatric dosage of an ASBTI is given every four hours. In someembodiments, the pediatric dosage of an ASBTI is given q.q.h. In someembodiments, the pediatric dosage of an ASBTI is given every other day.In some embodiments, the pediatric dosage of an ASBTI is given q.o.d. Insome embodiments, the pediatric dosage of an ASBTI is given three timesa week. In some embodiments, the pediatric dosage of an ASBTI is givent.i.w.

Provided in certain embodiments herein are methods and dosage forms(e.g., oral or rectal dosage form) for use in the treatment of apediatric cholestatic liver disease or pruritis, or lowering serum bileacid concentrations comprising a therapeutically effective amount of anASBTI, or a pharmaceutically acceptable salt thereof, and a carrier. Insome embodiments, provided herein is a method for treating cholestasisand/or a cholestatic liver disease comprising orally administering atherapeutically effective amount of a minimally absorbed ASBTI, or apharmaceutically acceptable salt thereof, to an individual in needthereof. In some embodiments, provided herein is a method for treatingcholestasis and/or a cholestatic liver disease comprising orallyadministering a therapeutically effective amount of a minimally absorbedASBTI, or a pharmaceutically acceptable salt thereof, to an individualin need thereof. In some embodiments, the ASBTI, or salt thereof is aminimally absorbed ASBTI. In specific embodiments, the dosage form is anenteric formulation, an ileal-pH sensitive release formulation, or asuppository or other suitable form.

In some embodiments, a composition for use in the treatment of apediatric cholestatic liver disease or pruritis, or lowering serum bileacid concentrations comprises at least one of a spreading agent or awetting agent. In some embodiments, the composition comprises anabsorption inhibitor. In some cases an absorption inhibitor is amucoadhesive agent (e.g., a mucoadhesive polymer). In certainembodiments, the mucoadhesive agent is selected from methyl cellulose,polycarbophil, polyvinylpyrrolidone, sodium carboxymethyl cellulose, andcombinations thereof. In some embodiments, the enteroendocrine peptidesecretion enhancing agent is covalently linked to the absorptioninhibitor. In certain embodiments, the pharmaceutical compositioncomprises an enteric coating. In some embodiments, a composition for usein treatment of cholestasis, a cholestatic liver disease or pruritisdescribed above comprises a carrier. In certain embodiments, the carrieris a rectally suitable carrier. In certain embodiments, anypharmaceutical composition described herein is formulated as asuppository, an enema solution, a rectal foam, or a rectal gel. In someembodiments, any pharmaceutical composition described herein comprisesan orally suitable carrier.

In some embodiments, a pediatric dosage form comprising an ASBTI isadministered orally. In some embodiments, the ASBTI is administered asan ileal-pH sensitive release formulation that delivers the ASBTI to thedistal ileum, colon and/or rectum of an individual. In some embodiments,the ASBTI is administered as an enterically coated formulation. In someembodiments, oral delivery of an ASBTI provided herein can includeformulations, as are well known in the art, to provide prolonged orsustained delivery of the drug to the gastrointestinal tract by anynumber of mechanisms. These include, but are not limited to, pHsensitive release from the dosage form based on the changing pH of thesmall intestine, slow erosion of a tablet or capsule, retention in thestomach based on the physical properties of the formulation, bioadhesionof the dosage form to the mucosal lining of the intestinal tract, orenzymatic release of the active drug from the dosage form. The intendedeffect is to extend the time period over which the active drug moleculeis delivered to the site of action (the ileum) by manipulation of thedosage form. Thus, enteric-coated and enteric-coated controlled releaseformulations are within the scope of the present invention. Suitableenteric coatings include cellulose acetate phthalate, polyvinylacetatephthalate, hydroxypropylmethylcellulose phthalate and anionic polymersof methacrylic acid and methacrylic acid methyl ester.

In some embodiments, the methods and compositions provided hereinfurther comprise administration of a bile acid sequestrant or binder forreducing gastrointestinal side effects. In some embodiments, methodscomprise administering a labile bile acid sequestrant, wherein thelabile bile acid sequestrant has a low affinity in the colon or rectumof the individual for at least one bile acid. In some embodiments, alabile bile acid sequestrant provided herein releases a bile acid in thecolon or the rectum of a human. In some embodiments, a labile bile acidsequestrant provided herein does not sequester a bile acid for excretionor elimination in feces. In some embodiments, a labile bile acidsequestrant provided herein is a non-systemic labile bile acidsequestrant. In some embodiments, non-systemic labile bile acidsequestrant is less than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45% absorbed systemically. In some embodiments,the labile bile acid sequestrant is lignin or a modified lignin. In someembodiments, the labile bile acid sequestrant is a polycationic polymeror copolymer. In certain embodiments, the labile bile acid sequestrantis a polymer or copolymer comprising one or more N-alkenyl-N-alkylamineresidues; one or more N,N,N-trialkyl-N—(N′-alkenylamino)alkyl-azaniumresidues; one or more N,N,N-trialkyl-N-alkenyl-azanium residues; one ormore alkenyl-amine residues; cholestyramine, cholestipol, orcholesevelamor a combination thereof.

In some embodiments of the methods described above, a pediatric dosageform comprising an ASBTI is administered before ingestion of food. Insome embodiments of the methods described above, a pediatric dosage formcomprising an ASBTI is administered with or after ingestion of food.

In some embodiments, the methods provided herein further compriseadministration of vitamin supplements to compensate for reduceddigestion of vitamins, in particular fat-soluble vitamins, in anindividual with a pediatric cholestatic liver disease, pruritis, orelevated serum bile acid levels or concentrations. In some embodiments,the vitamin supplements comprise fat-soluble vitamins. In someembodiments, the fat-soluble vitamins are vitamin A, D, E, or K.

In some cases, for any of the methods described above, administration ofan ASBTI reduces intraenterocyte bile acids/salts in an individual inneed thereof. In some embodiments, the methods described herein reduceaccumulation of bile acids/salts in ileal enterocytes of an individualin need thereof. In some cases, for any of the methods described above,administration of an ASBTI inhibits transport of bile acids/salts fromileal lumen into enterocytes of an individual in need thereof. In somecases, for any of the methods described above, administration of anASBTI increases ileal luminal bile acids/salts in an individual in needthereof. In some cases, for any of the methods described above,administration of an ASBTI reduces damage to intestinal (e.g., ilealcells) or hepatocellular (e.g., liver cells) architecture associatedwith a pediatric cholestatic liver disease or elevated serum or hepaticbile acid concentrations in an individual in need thereof. In somecases, for any of the methods described above, administration of anASBTI regenerates intestinal lining or liver cells that have beeninjured by cholestasis and/or by a cholestatic liver disease in anindividual suffering from a cholestatic liver disease.

In some embodiments, provided herein are methods for the treatment of apediatric cholestatic liver disease comprising administration of atherapeutically effective amount of a pediatric dosage form comprising acombination of an ASBTI and ursodiol to an individual in need thereof.In some embodiments, provided herein are methods for the treatment of apediatric cholestatic liver disease comprising administration of atherapeutically effective amount of a combination of an ASBTI and aresin or sequestrant for absorbing bile acids to an individual in needthereof. In some embodiments, an ASBTI is administered in combinationwith one or more agent selected from the group consisting of ursodiol,norursodiol, UDCA, ursodeoxycholic acid, chenodeoxycholic acid, cholicacid, taurocholic acid, ursocholic acid, glycocholic acid,glycodeoxycholic acid, taurodeoxycholic acid, taurocholate,glycochenodeoxycholic acid, tauroursodeoxycholic acid,cholestyramine/resins, antihistamine agents (e.g., hydroxyzine,diphenhydamine), rifampin, nalaxone, Phenobarbital, dronabinol (CB 1agonist), methotrexate, corticosteroids, cyclosporine, colchicines,TPGS—vitamin A, D, E, or K optionally with polyethylene glycol, zinc, aresin or sequestrant for absorbing bile acids.

In some embodiments, the methods provided herein further comprisepartial external biliary diversion (PEBD) therapy.

Provided in some embodiments herein is a kit comprising any compositiondescribed herein (e.g., a pharmaceutical composition formulated forrectal administration) and a device for localized delivery within therectum or colon. In certain embodiments, the device is a syringe, bag,or a pressurized container.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Oral administration of 264W94 dose-dependently increased bileacids in the feces. Fecal bile acid concentrations were elevated up to6.5 fold with an ED₅₀ of 0.17 mg/kg, when compared to vehicle treatedrats. Fecal NEFA also slightly increased in 264W94 treated rats. Plasmabile acid concentrations were decreased dose-dependently in 264W94treated rats.

FIG. 2. Plasma bile acid levels of ZDF rats after administration ofascending doses of SC-435 and LUM002. Male ZDF rats (n=4) wereadministered vehicle, SC-435 (1, 10 or 30 mg/kg) or LUM002 (0.3, 1, 3,10 or 30 mg/kg) by oral gavage twice a day for 2 weeks. Plasma bile acidlevels were determined at the end of the second week. Data are expressedas mean values±SEM.

FIG. 3. Serum bile acid (SBA) analysis of healthy subjects afteradministration of ascending multiple oral doses of LUM001 a randomized,double-blind, placebo-controlled study. Shown in the graphs are datafrom the 0.5 (n=16), 1.0 (n=8), 2.5 (n=8), 5.0 (n=8) and 10 (n=8) mgdosing groups. On Day 1, blood was drawn for baseline SBA atapproximately 30 minutes before and after breakfast and 30 minutes afterlunch and dinner. Samples were obtained on day 14.

FIG. 4. Fecal bile acid analysis of healthy subjects afteradministration of ascending multiple oral doses of LUM001 a randomized,double-blind, placebo-controlled study. Fecal samples were collected forall panels except the dose-titration panel, 2.5 (2) and 5 mg (2), onDays 9 through 14 and 23 through 28.

FIG. 5. Fasting serum bile acid levels and morning post-prandial peak inchildren under the age of 12. LUM001 was administered once-a-day (QD) inthe morning for fourteen days. The placebo patients had an averagefasting serum bile acid level of 8.6 μmol/L and a post-prandial peakserum bile acid level of 11.9 μmol/L. For the LUM001 treated patientsthe values were 6.5 μmol/L and 9.2, respectively, representing a 24% and23% decrease.

DETAILED DESCRIPTION OF THE INVENTION

Bile acids/salts play a critical role in activating digestive enzymesand solubilizing fats and fat-soluble vitamins and are involved inliver, biliary, and intestinal disease. Bile acids are synthesized inthe liver by a multistep, multiorganelle pathway. Hydroxyl groups areadded to specific sites on the steroid structure, the double bond of thecholesterol B ring is reduced and the hydrocarbon chain is shortened bythree carbon atoms resulting in a carboxyl group at the end of thechain. The most common bile acids are cholic acid and chenodeoxycholicacid (the “primary bile acids”). Before exiting the hepatocytes andforming bile, the bile acids are conjugated to either glycine (toproduce glycocholic acid or glycochenodeoxycholic acid) or taurine (toproduce taurocholic acid or taurochenodeoxycholic acid). The conjugatedbile acids are called bile salts and their amphipathic nature makes themmore efficient detergents than bile acids. Bile salts, not bile acids,are found in bile.

Bile salts are excreted by the hepatocytes into the canaliculi to formbile. The canaliculi drain into the right and left hepatic ducts and thebile flows to the gallbladder. Bile is released from the gallbladder andtravels to the duodenum, where it contributes to the metabolism anddegradation of fat. The bile salts are reabsorbed in the terminal ileumand transported back to the liver via the portal vein. Bile salts oftenundergo multiple enterohepatic circulations before being excreted viafeces. A small percentage of bile salts may be reabsorbed in theproximal intestine by either passive or carrier-mediated transportprocesses. Most bile salts are reclaimed in the distal ileum by asodium-dependent apically located bile acid transporter referred to asapical sodium-dependent bile acid transporter (ASBT). At the basolateralsurface of the enterocyte, a truncated version of ASBT is involved invectorial transfer of bile acids/salts into the portal circulation.Completion of the enterohepatic circulation occurs at the basolateralsurface of the hepatocyte by a transport process that is primarilymediated by a sodium-dependent bile acid transporter. Intestinal bileacid transport plays a key role in the enterohepatic circulation of bilesalts. Molecular analysis of this process has recently led to importantadvances in our understanding of the biology, physiology andpathophysiology of intestinal bile acid transport.

Within the intestinal lumen, bile acid concentrations vary, with thebulk of the reuptake occurring in the distal intestine. Bile acids/saltsalter the growth of bacterial flora in the gut. Described herein arecertain compositions and methods that control bile acid concentrationsin the intestinal lumen, thereby controlling the hepatocellular damagecaused by bile acid accumulation in the liver.

In another aspect, the compositions and methods provided herein increasebile acid concentrations in the gut. The increased concentrations ofbile acids/salts stimulate subsequent secretion of factors that protectand control integrity of the intestine when it is injured by pediatriccholestasis and/or a pediatric cholestatic liver disease (e.g., apediatric cholestatic liver disease associated with pruritis, or apediatric cholestatic liver disease associated with elevated serum bileacid concentrations or hepatic bile acid concentrations).

In yet another aspect, the compositions and methods described hereinhave an advantage over systemically absorbed agents. The compositionsand methods described herein utilize ASBT inhibitors that are notsystemically absorbed. Thus the compositions are effective withoutleaving the gut lumen, thereby reducing any toxicity and/or side effectsassociated with systemic absorption. The pediatric formulationsdescribed herein have an advantage over existing adult dosage forms anddosages to reduce harmful side effects and increase compliance.

In a further aspect, the compositions and methods described hereinstimulate the release of enteroendocrine hormones GLP-2 and PYY.Increased secretion of GLP-2 or PYY allows for prevention or treatmentof pediatric cholestasis and/or a pediatric cholestatic liver disease bycontrolling the adaptive process, attenuating intestinal injury,reducing bacterial translocation, inhibiting the release of free radicaloxygen, inhibiting production of proinflammatory cytokines, or anycombination thereof.

Described herein is the use of inhibitors of the ASBT or anyrecuperative bile salt transporter that are active in thegastrointestinal (GI) tract for treating or preventing pediatriccholestasis and/or a pediatric cholestatic liver disease in anindividual in need thereof. In certain embodiments, described herein isthe use of inhibitors of the ASBT or any recuperative bile salttransporter that are active in the gastrointestinal (GI) tract fortreating or preventing pruritis in an individual in need thereof. Incertain embodiments, described herein is the use of inhibitors of theASBT or any recuperative bile salt transporter that are active in thegastrointestinal (GI) tract for lowering serum bile acid concentrationsor hepatic bile acid concentrations in an individual in need thereof. Incertain embodiments, the methods provided herein comprise administeringa therapeutically effective amount of an ASBTI to an individual in needthereof. In some embodiments, such ASBT inhibitors are not systemicallyabsorbed. In some of such embodiments, such bile salt transportinhibitors include a moiety or group that prevents, reduces or inhibitsthe systemic absorption of the compound in vivo. In some embodiments, acharged moiety or group on the compounds prevents, reduces or inhibitsthe compounds from leaving the gastrointestinal tract and reduces therisk of side effects due to systemic absorption. In some otherembodiments, such ASBT inhibitors are systemically absorbed. In someembodiments, the ASBTI provided herein are formulated for non-systemicdelivery to the distal ileum. In some embodiments, an ASBTI is minimallyabsorbed. In some embodiments, an ASBTI is non-systemically administeredto the colon or the rectum of an individual in need thereof.

In some embodiments, such ASBT inhibitors are not systemically absorbed.In some of such embodiments, such bile salt transport inhibitors includea moiety or group that prevents, reduces or inhibits the systemicabsorption of the compound in vivo. In some embodiments, a chargedmoiety or group on the compounds prevents, reduces or inhibits thecompounds from leaving the gastrointestinal tract and reduces the riskof side effects due to systemic absorption. In some other embodiments,such ASBT inhibitors are systemically absorbed. In some embodiments, theASBTI are formulated for non-systemic delivery to the distal ileum. Insome embodiments, an ASBTI is minimally absorbed. In some embodiments,an ASBTI is non-systemically administered to the colon or the rectum ofan individual in need thereof.

In some embodiments, less than 50%, less than 40%, less than 30%, lessthan 20%, less than 10%, less than 9%, less than 8%, less than 7%, lessthan 6%, less than 5%, less than 4%, less than 3%, less than 2%, or lessthan 1% of the ASBTI is systemically absorbed. In certain embodiments,ASBTIs described herein inhibit scavenging of bile salts by recuperativebile acid salt transporters in the distal gastrointestinal tract (e.g.,the distal ileum, the colon and/or the rectum).

In some instances, the inhibition of bile salt recycling results inhigher concentrations of bile salts in the lumen of the distalgastrointestinal tract or portions thereof (e.g., the distal small boweland/or colon and/or rectum). As used herein, the distal gastrointestinaltract includes the region from the distal ileum to the anus. In someembodiments, the compounds described herein reduce intraenterocyte bileacids/salts or accumulation thereof. In some embodiments, the compoundsdescribed herein reduce damage to hepatocellular or intestinalarchitecture associated with cholestasis and/or a cholestatic liverdisease. Mammalian microbiome, bile acid pools and metabolicinteractions

The integrated metabolism of the bile acid pools in the intestinal lumenlends itself to complex biochemical interactions between host andmicrobiome symbionts.

Bile acids/salts are synthesized from cholesterol in the liver by amulti-enzyme coordinated process and are crucial for the absorption ofdietary fats and lipid-soluble vitamins in the intestine. Bileacids/salts play a role in maintaining the intestinal barrier functionto prevent intestinal bacterial overgrowth and translocation, as well asinvasion of underlying tissues by enteric bacteria.

Under normal conditions (i.e., when an individual is not suffering frompediatric cholestasis and/or a pediatric cholestatic liver disease),symbiotic gut microorganisms (microbiome) interact closely with thehost's metabolism and are important determinants of health. Manybacterial species in the gut are capable of modifying and metabolizingbile acids/salts and the gut flora affects systemic processes such asmetabolism and inflammation.

Bile acids/salts have strong antimicrobial and antiviraleffects—deficiency leads to bacterial overgrowth and increaseddeconjugation, leading to less ileal resorption. In animals, conjugatedbile acid feeding abolishes bacterial overgrowth, decreases bacterialtranslocation to lymph nodes and reduces endotoxemia.

Accordingly, the methods and compositions described herein allow forreplacement, displacement, and/or redirection of bile acids/salts todifferent areas of the gastrointestinal tract thereby affecting (e.g.,inhibiting or slowing) growth of microorganisms that may causeinfection-associated cholestasis and/or a cholestatic liver disease.

Classes of Pediatric Cholestatic Liver Disease

As used herein, “cholestasis” means the disease or symptoms comprisingimpairment of bile formation and/or bile flow. As used herein,“cholestatic liver disease” means a liver disease associated withcholestasis. Cholestatic liver diseases are often associated withjaundice, fatigue, and pruritis. Biomarkers of cholestatic liver diseaseinclude elevated serum bile acid concentrations, elevated serum alkalinephosphatase (AP), elevated gamma-glutamyltranspeptidease, elevatedconjugated hyperbilirubinemia, and elevated serum cholesterol.

Cholestatic liver disease can be sorted clinicopathologically betweentwo principal categories of obstructive, often extrahepatic,cholestasis, and nonobstructive, or intrahepatic, cholestasis. In theformer, cholestasis results when bile flow is mechanically blocked, asby gallstones or tumor, or as in extrahepatic biliary atresia.

The latter group who has nonobstructive intrahepatic cholestasis in turnfall into two principal subgroups. In the first subgroup, cholestasisresults when processes of bile secretion and modification, or ofsynthesis of constituents of bile, are caught up secondarily inhepatocellular injury so severe that nonspecific impairment of manyfunctions can be expected, including those subserving bile formation. Inthe second subgroup, no presumed cause of hepatocellular injury can beidentified. Cholestasis in such patients appears to result when one ofthe steps in bile secretion or modification, or of synthesis ofconstituents of bile, is constitutively damages. Such cholestasis isconsidered primary.

Accordingly, provided herein are methods and compositions forstimulating epithelial proliferation and/or regeneration of intestinallining and/or enhancement of the adaptive processes in the intestine inindividuals with cholestasis and/or a cholestatic liver disease. In someof such embodiments, the methods comprise increasing bile acidconcentrations and/or GLP-2 concentrations in the intestinal lumen.

Hypercholemia, and elevated levels of AP (alkaline phosphatase), LAP(leukocyte alkaline phosphatase), gamma GT (gamma-glutamyltranspeptidase), and 5′-nucleotidase are biochemical hallmarks ofcholestasis and cholestatic liver disease. Accordingly, provided hereinare methods and compositions for stimulating epithelial proliferationand/or regeneration of intestinal lining and/or enhancement of theadaptive processes in the intestine in individuals with hypercholemia,and elevated levels of AP (alkaline phosphatase), LAP (leukocytealkaline phosphatase), gamma GT (gamma-glutamyl transpeptidase or GGT),and/or 5′-nucleotidase. In some of such embodiments, the methodscomprise increasing bile acid concentrations concentrations in theintestinal lumen. Further provided herein, are methods and compositionsfor reducing hypercholemia, and elevated levels of AP (alkalinephosphatase), LAP (leukocyte alkaline phosphatase), gamma GT(gamma-glutamyl transpeptidase), and 5′-nucleotidase comprising reducingoverall bile acid load by excreting bile acid in the feces.

Pruritus is often associated with pediatric cholestasis and pediatriccholestatic liver diseases. It has been suggested that pruritus resultsfrom bile salts acting on peripheral pain afferent nerves. The degree ofpruritus varies with the individual (i.e., some individuals are moresensitive to elevated levels of bile acids/salts). Administration ofagents that reduce serum bile acid concentrations has been shown toreduce pruritus in certain individuals. Accordingly, provided herein aremethods and compositions for stimulating epithelial proliferation and/orregeneration of intestinal lining and/or enhancement of the adaptiveprocesses in the intestine in individuals with pruritus. In some of suchembodiments, the methods comprise increasing bile acid concentrations inthe intestinal lumen. Further provided herein, are methods andcompositions for treating pruritus comprising reducing overall bile acidload by excreting bile acid in the feces.

Another symptom of pediatric cholestasis and pediatric cholestatic liverdisease is the increase in serum concentration of conjugated bilirubin.Elevated serum concentrations of conjugated bilirubin result in jaundiceand dark urine. The magnitude of elevation is not diagnosticallyimportant as no relationship has been established between serum levelsof conjugated bilirubin and the severity of cholestasis and cholestaticliver disease. Conjugated bilirubin concentration rarely exceeds 30mg/dL. Accordingly, provided herein are methods and compositions forstimulating epithelial proliferation and/or regeneration of intestinallining and/or enhancement of the adaptive processes in the intestine inindividuals with elevated serum concentrations of conjugated bilirubin.In some of such embodiments, the methods comprise increasing bile acidconcentrations in the intestinal lumen. Further provided herein, aremethods and compositions for treating elevated serum concentrations ofconjugated bilirubin comprising reducing overall bile acid load byexcreting bile acid in the feces.

Increased serum concentration of nonconjugated bilirubin is alsoconsidered diagnostic of cholestasis and cholestatic liver disease.Portions of serum bilirubin and covalently bound to albumin (deltabilirubin or biliprotein). This fraction may account for a largeproportion of total bilirubin in patients with cholestatic jaundice. Thepresence of large quantities of delta bilirubin indicates long-standingcholestasis. Delta bilirubin in cord blood or the blood of a newborn isindicative of pediatric cholestasis/cholestatic liver disease thatantedates birth. Accordingly, provided herein are methods andcompositions for stimulating epithelial proliferation and/orregeneration of intestinal lining and/or enhancement of the adaptiveprocesses in the intestine in individuals with elevated serumconcentrations of nonconjugated bilirubin or delta bilirubin. In some ofsuch embodiments, the methods comprise increasing bile acidconcentrations in the intestinal lumen. Further provided herein, aremethods and compositions for treating elevated serum concentrations ofnonconjugated bilirubin and delta bilirubin comprising reducing overallbile acid load by excreting bile acid in the feces.

Pediatric cholestasis and cholestatic liver disease results inhypercholemia. During metabolic cholestasis, the hepatocytes retainsbile salts. Bile salts are regurgitated from the hepatocyte into theserum, which results in an increase in the concentration of bile saltsin the peripheral circulation. Furthermore, the uptake of bile saltsentering the liver in portal vein blood is inefficient, which results inspillage of bile salts into the peripheral circulation. Accordingly,provided herein are methods and compositions for stimulating epithelialproliferation and/or regeneration of intestinal lining and/orenhancement of the adaptive processes in the intestine in individualswith hypercholemia. In some of such embodiments, the methods compriseincreasing bile acid concentrations in the intestinal lumen. Furtherprovided herein, are methods and compositions for treating hypercholemiacomprising reducing overall bile acid load by excreting bile acid in thefeces.

Hyperlipidemia is characteristic of some but not all cholestaticdiseases. Serum cholesterol is elevated in cholestasis due to thedecrease in circulating bile salts which contribute to the metabolismand degradation of cholesterol. Cholesterol retention is associated withan increase in membrane cholesterol content and a reduction in membranefluidity and membrane function. Furthermore, as bile salts are themetabolic products of cholesterol, the reduction in cholesterolmetabolism results in a decrease in bile acid/salt synthesis. Serumcholesterol observed in children with cholestasis ranges between about1,000 mg/dL and about 4,000 mg/dL. Accordingly, provided herein aremethods and compositions for stimulating epithelial proliferation and/orregeneration of intestinal lining and/or enhancement of the adaptiveprocesses in the intestine in individuals with hyperlipidemia. In someof such embodiments, the methods comprise increasing bile acidconcentrations concentrations in the intestinal lumen. Further providedherein, are methods and compositions for treating hyperlipidemiacomprising reducing overall bile acid load by excreting bile acid in thefeces.

In individuals with pediatric cholestasis and pediatric cholestaticliver diseases, xanthomas develop from the deposition of excesscirculating cholesterol into the dermis. The development of xanthomas ismore characteristic of obstructive cholestasis than of hepatocellularcholestasis. Planar xanthomas first occur around the eyes and then inthe creases of the palms and soles, followed by the neck. Tuberousxanthomas are associated with chronic and long-term cholestasis.Accordingly, provided herein are methods and compositions forstimulating epithelial proliferation and/or regeneration of intestinallining and/or enhancement of the adaptive processes in the intestine inindividuals with xanthomas. In some of such embodiments, the methodscomprise increasing bile acid concentrations in the intestinal lumen.Further provided herein, are methods and compositions for treatingxanthomas comprising reducing overall bile acid load by excreting bileacid in the feces.

In children with chronic cholestasis, one of the major consequences ofpediatric cholestasis and pediatric cholestatic liver disease is failureto thrive. Failure to thrive is a consequence of reduced delivery ofbile salts to the intestine, which contributes to inefficient digestionand absorption of fats, and reduced uptake of vitamins (vitamins E, D,K, and A are all malabsorbed in cholestasis). Furthermore, the deliveryof fat into the colon can result in colonic secretion and diarrhea.Treatment of failure to thrive involves dietary substitution andsupplementation with long-chain triglycerides, medium-chaintriglycerides, and vitamins. Ursodeoxycholic acid, which is used totreat some cholestatic conditions, does not form mixed micelles and hasno effect on fat absorption. Accordingly, provided herein are methodsand compositions for stimulating epithelial proliferation and/orregeneration of intestinal lining and/or enhancement of the adaptiveprocesses in the intestine in individuals (e.g., children) with failureto thrive. In some of such embodiments, the methods comprise increasingbile acid concentrations in the intestinal lumen. Further providedherein, are methods and compositions for treating failure to thrivecomprising reducing overall bile acid load by excreting bile acid in thefeces.

Symptoms of pediatric cholestasis and pediatric cholestatic liverdisease have been treated with choleretic agents (e.g., ursodiol),phenobarbitols, corticosteroids (e.g., prednisone and budesonide),immunosuppressive agents (e.g., azathioprine, cyclosporin A,methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate,tamoxifen, and lamivudine. Accordingly, in some embodiments, any of themethods disclosed herein further comprise administration of anadditional active agent selected from: choleretic agents (e.g.,ursodiol), phenobarbitols, corticosteroids (e.g., prednisone andbudesonide), immunosuppressive agents (e.g., azathioprine, cyclosporinA, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate,tamoxifen, lamivudine, and combinations thereof. In some embodiments,the methods are used to treat individuals that are non-responsive totreatment with choleretic agents (e.g., ursodiol), phenobarbitols,corticosteroids (e.g., prednisone and budesonide), immunosuppressiveagents (e.g., azathioprine, cyclosporin A, methotrexate, chlorambuciland mycophenolate), sulindac, bezafibrate, tamoxifen, lamivudine, andcombinations thereof. In some embodiments, the methods are used to treatindividuals that are non-responsive to treatment with choleretic agents.In some embodiments, the methods are used to treat individuals that arenon-responsive to treatment with ursodiol.

Progressive Familial Intrahepatic Cholestasis (PFIC) PFIC1

PFIC1 (also known as, Byler disease or FIC1 deficiency) is associatedwith mutations in the ATP8B 1 gene (also designated as FIC1). This gene,which encodes a P-type ATPase, is located on human chromosome 18 and isalso mutated in the milder phenotype, benign recurrent intrahepaticcholestasis type 1 (BRIC 1) and in Greenland familial cholestasis. FIC1protein is located on the canalicular membrane of the hepatocyte butwithin the liver it is mainly expressed in cholangiocytes. P-type ATPaseappears to be an aminophospholipid transporter responsible formaintaining the enrichment of phosphatidylserine andphophatidylethanolamine on the inner leaflet of the plasma membrane incomparison of the outer leaflet. The asymmetric distribution of lipidsin the membrane bilayer plays a protective role against high bile saltconcentrations in the canalicular lumen. The abnormal protein functionmay indirectly disturb the biliary secretion of bile acids. Theanomalous secretion of bile acids/salts leads to hepatocyte bile acidoverload.

PFIC-1 typically presents in infants (e.g., age 6-18 months). Theinfants may show signs of pruritus, jaundice, abdominal distension,diarrhea, malnutrition, and shortened stature. Biochemically,individuals with PFIC-1 have elevated serum transaminases, elevatedbilirubin, elevated serum bile acid levels, and low levels of gammaGT.The individual may also have liver fibrosis. Individuals with PFIC-1typically do not have bile duct proliferation. Most individuals withPFIC-1 will develop end-stage liver disease by 10 years of age. Nomedical treatments have proven beneficial for the long term treatment ofPFIC-1. In order to reduce extrahepatic symptoms (e.g., malnutrition andfailure to thrive), children are often administered medium chaintriglycerides and fat-soluble vitamins. Ursodiol has not beendemonstrated as effective in individuals with PFIC-1.

Disclosed herein, in certain embodiments, are methods of treating PFIC-1in an individual in need thereof comprising non-systemicallyadministering a therapeutically effective amount of an ApicalSodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or apharmaceutically acceptable salt thereof. In some embodiments, such ASBTinhibitors are not systemically absorbed. In some of such embodiments,such bile salt transport inhibitors include a moiety or group thatprevents, reduces or inhibits the systemic absorption of the compound invivo. In some embodiments, a charged moiety or group on the compoundsprevents, reduces or inhibits the compounds from leaving thegastrointestinal tract and reduces the risk of side effects due tosystemic absorption. In some other embodiments, such ASBT inhibitors aresystemically absorbed. In some embodiments, the ASBTI are formulated fornon-systemic delivery to the distal ileum. In some embodiments, an ASBTIis minimally absorbed. In some embodiments, an ASBTI is non-systemicallyadministered to the colon or the rectum of an individual in needthereof. In some embodiments, the methods further comprise administeringa therapeutically-effective amount of a secondary bile acid (e.g.,ursodiol), a corticosteroid (e.g., prednisone and budesonide), animmunosuppressive agent (e.g., azathioprine, cyclosporin A,methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate,tamoxifen, lamivudine or any combination thereof.

PFIC2

PFIC2 (also known as, Byler Syndrome or BSEP deficiency) is associatedwith mutations in the ABCB11 gene (also designated BSEP). The ABCB11gene encodes the ATP-dependent canalicular bile salt export pump (BSEP)of human liver and is located on human chromosome 2. BSEP protein,expressed at the hepatocyte canalicular membrane, is the major exporterof primary bile acids/salts against extreme concentration gradients.Mutations in this protein are responsible for the decreased biliary bilesalt secretion described in affected patients, leading to decreased bileflow and accumulation of bile salts inside the hepatocyte with ongoingsevere hepatocellular damage.

PFIC-2 typically presents in infants (e.g., age 6-18 months). Theinfants may show signs of pruritus. Biochemically, individuals withPFIC-2 have elevated serum transaminases, elevated bilirubin, elevatedserum bile acid levels, and low levels of gammaGT. The individual mayalso have portal inflammation and giant cell hepatitis. Further,individuals often develop hepatocellular carcinoma. No medicaltreatments have proven beneficial for the long term treatment of PFIC-1.In order to reduce extrahepatic symptoms (e.g., malnutrition and failureto thrive), children are often administered medium chain triglyceridesand fat-soluble vitamins. Ursodiol has not been demonstrated aseffective in individuals with PFIC-2.

Disclosed herein, in certain embodiments, are methods of treating PFIC-2in an individual in need thereof comprising non-systemicallyadministering a therapeutically effective amount of an ApicalSodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or apharmaceutically acceptable salt thereof. In some embodiments, such ASBTinhibitors are not systemically absorbed. In some of such embodiments,such bile salt transport inhibitors include a moiety or group thatprevents, reduces or inhibits the systemic absorption of the compound invivo. In some embodiments, a charged moiety or group on the compoundsprevents, reduces or inhibits the compounds from leaving thegastrointestinal tract and reduces the risk of side effects due tosystemic absorption. In some other embodiments, such ASBT inhibitors aresystemically absorbed. In some embodiments, the ASBTI are formulated fornon-systemic delivery to the distal ileum. In some embodiments, an ASBTIis minimally absorbed. In some embodiments, an ASBTI is non-systemicallyadministered to the colon or the rectum of an individual in needthereof. In some embodiments, the methods further comprise administeringa therapeutically-effective amount of a secondary bile acid (e.g.,ursodiol), a corticosteroid (e.g., prednisone and budesonide), animmunosuppressive agent (e.g., azathioprine, cyclosporin A,methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate,tamoxifen, lamivudine or any combination thereof.

PFIC3

PFIC3 (also known as MDR3 deficiency) is caused by a genetic defect inthe ABCB4 gene (also designated MDR3) located on chromosome 7. Class IIIMultidrug Resistance (MDR3) P-glycoprotein (P-gp), is a phospholipidtranslocator involved in biliary phospholipid (phosphatidylcholine)excretion in the canlicular membrane of the hepatocyte. PFIC3 resultsfrom the toxicity of bile in which detergent bile salts are notinactivated by phospholipids, leading to bile canaliculi and biliaryepithelium injuries.

PFIC-3 also presents in early childhood. As opposed to PFIC-1 andPFIC-2, individuals have elevated gammaGT levels. Individuals also haveportal inflammation, fibrosis, cirrhosis, and massive bile ductproliferation. Individuals may also develop intrahepatic gallstonedisease. Ursodiol has been effective in treating or ameliorating PFIC-3.

Disclosed herein, in certain embodiments, are methods of treating PFIC-3in an individual in need thereof comprising non-systemicallyadministering a therapeutically effective amount of an ApicalSodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or apharmaceutically acceptable salt thereof. In some embodiments, such ASBTinhibitors are not systemically absorbed. In some of such embodiments,such bile salt transport inhibitors include a moiety or group thatprevents, reduces or inhibits the systemic absorption of the compound invivo. In some embodiments, a charged moiety or group on the compoundsprevents, reduces or inhibits the compounds from leaving thegastrointestinal tract and reduces the risk of side effects due tosystemic absorption. In some other embodiments, such ASBT inhibitors aresystemically absorbed. In some embodiments, the ASBTI are formulated fornon-systemic delivery to the distal ileum. In some embodiments, an ASBTIis minimally absorbed. In some embodiments, an ASBTI is non-systemicallyadministered to the colon or the rectum of an individual in needthereof. In some embodiments, the methods further comprise administeringa therapeutically-effective amount of a secondary bile acid (e.g.,ursodiol), a corticosteroid (e.g., prednisone and budesonide), animmunosuppressive agent (e.g., azathioprine, cyclosporin A,methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate,tamoxifen, lamivudine or any combination thereof.

Benign Recurrent Intrahepatic Cholestasis (BRIC) BRIC 1

BRIC 1 is caused by a genetic defect of the FIC1 protein in thecanalicular membrane of hepatocytes. BRIC 1 is typically associated withnormal serum cholesterol and γ-glutamyltranspeptidase levels, butelevated serum bile salts. Residual FIC1 expression and function isassociated with BRIC 1. Despite recurrent attacks of cholestasis orcholestatic liver disease, there is no progression to chronic liverdisease in a majority of patients. During the attacks, the patients areseverely jaundiced and have pruritis, steatorrhea, and weight loss. Somepatients also have renal stones, pancreatitis, and diabetes.

BRIC 2

BRIC2 is caused by mutations in ABCB11, leading to defective BSEPexpression and/or function in the canalicular membrane of hepatocytes.

BRIC 3

BRIC3 is related to the defective expression and/or function of MDR3 inthe canalicular membrane of hepatocytes. Patients with MDR3 deficiencyusually display elevated serum γ-glutamyltranspeptidase levels in thepresence of normal or slightly elevated bile acid levels.

Dubin-Johnson Syndrome (DJS)

DJS is characterized by conjugated hyperbilirubinemia due to inheriteddysfunction of MRP2. Hepatic function is preserved in affected patients.Several different mutations have been associated with this condition,resulting either in the complete absence of immunohistochemicallydetectable MRP2 in affected patients or impaired protein maturation andsorting.

Acquired Cholestatic Disease Pediatric Primary Sclerosing Cholangitis(PSC)

Pediatric PSC is a chronic inflammatory hepatic disorder slowlyprogressing to end stage liver failure in most of the affected patients.In pediatric PSC inflammation, fibrosis and obstruction of large andmedium sized intra- and extrahepatic ductuli is predominant.

Gallstone Disease

Gallstone disease is one of the most common and costly of all digestivediseases with a prevalence of up to 17% in Caucasian women. Cholesterolcontaining gallstones are the major form of gallstones andsupersaturation of bile with cholesterol is therefore a prerequisite forgallstone formation. ABCB4 mutations may be involved in the pathogenesisof cholesterol gallstone disease.

Drug Induced Cholestasis

Inhibition of BSEP function by drugs is an important mechanism ofdrug-induced cholestasis, leading to the hepatic accumulation of bilesalts and subsequent liver cell damage. Several drugs have beenimplicated in BSEP inhibition. Most of these drugs, such as rifampicin,cyclosporine, glibenclamide, or troglitazone directly cis-inhibitATP-dependent taurocholate transport in a competitive manner, whileestrogen and progesterone metabolites indirectly trans-inhibits Bsepafter secretion into the bile canaliculus by Mrp2. Alternatively,drug-mediated stimulation of MRP2 can promote cholestasis or cholestaticliver disease by changing bile composition.

Total Parenteral Nutrition Associated Cholestasis

TPNAC is one of the most serious clinical scenarios where cholestasis orcholestatic liver disease occurs rapidly and is highly linked with earlydeath. Infants, who are usually premature and who have had gutresections are dependent upon TPN for growth and frequently developcholestasis or cholestatic liver disease that rapidly progresses tofibrosis, cirrhosis, and portal hypertension, usually before 6 months oflife. The degree of cholestasis or cholestatic liver disease and chanceof survival in these infants have been linked to the number of septicepisodes, likely initiated by recurrent bacterial translocation acrosstheir gut mucosa. Although there are also cholestatic effects from theintravenous formulation in these infants, septic mediators likelycontribute the most to altered hepatic function.

Alagille Syndrome

Alagille syndrome is a genetic disorder that affects the liver and otherorgans. It often presents during infancy (e.g., age 6-18 months) throughearly childhood (e.g., age 3-5 years) and may stabilize after the age of10. Symptoms may include chronic progressive cholestasis, ductopenia,jaundice, pruritus, xanthomas, congenital heart problems, paucity ofintrahepatic bile ducts, poor linear growth, hormone resistance,posterior embryotoxon, Axenfeld anomaly, retinitis pigmentosa, pupillaryabnormalities, cardiac murmur, atrial septal defect, ventricular septaldefect, patent ductus arteriosus, and Tetralogy of Fallot. Individualsdiagnosed with Alagille syndrome have been treated with ursodiol,hydroxyzine, cholestyramine, rifampicin, and phenobarbitol. Due to areduced ability to absorb fat-soluble vitamins, individuals withAlagille Syndrome are further administered high dose multivitamins.

Disclosed herein, in certain embodiments, are methods of treatingAlagille syndrome in an individual in need thereof comprisingnon-systemically administering a therapeutically effective amount of anASBTI or a pharmaceutically acceptable salt thereof. In someembodiments, such ASBT inhibitors are not systemically absorbed. In someof such embodiments, such bile salt transport inhibitors include amoiety or group that prevents, reduces or inhibits the systemicabsorption of the compound in vivo. In some embodiments, a chargedmoiety or group on the compounds prevents, reduces or inhibits thecompounds from leaving the gastrointestinal tract and reduces the riskof side effects due to systemic absorption. In some other embodiments,such ASBT inhibitors are systemically absorbed. In some embodiments, theASBTI are formulated for non-systemic delivery to the distal ileum. Insome embodiments, an ASBTI is minimally absorbed. In some embodiments,an ASBTI is non-systemically administered to the colon or the rectum ofan individual in need thereof. In some embodiments, the methods furthercomprise administering a therapeutically-effective amount of a secondarybile acid (e.g., ursodiol), a corticosteroid (e.g., prednisone andbudesonide), an immunosuppressive agent (e.g., azathioprine, cyclosporinA, methotrexate, chlorambucil and mycophenolate), sulindac, bezafibrate,tamoxifen, lamivudine or any combination thereof.

Biliary Atresia

Biliary atresia is a life-threatening condition in infants in which thebile ducts inside or outside the liver do not have normal openings. Withbiliary atresia, bile becomes trapped, builds up, and damages the liver.The damage leads to scarring, loss of liver tissue, and cirrhosis.Without treatment, the liver eventually fails and the infant needs aliver transplant to stay alive. The two types of biliary atresia arefetal and perinatal. Fetal biliary atresia appears while the baby is inthe womb. Perinatal biliary atresia is much more common and does notbecome evident until 2 to 4 weeks after birth.

Post-Kasai Biliary Atresia

Biliary atresia is treated with surgery called the Kasai procedure or aliver transplant. The Kasai procedure is usually the first treatment forbiliary atresia. During a Kasai procedure, the pediatric surgeon removesthe infant's damaged bile ducts and brings up a loop of intestine toreplace them. While the Kasai procedure can restore bile flow andcorrect many problems caused by biliary atresia, the surgery doesn'tcure biliary atresia. If the Kasai procedure is not successful, infantsusually need a liver transplant within 1 to 2 years. Even after asuccessful surgery, most infants with biliary atresia slowly developcirrhosis over the years and require a liver transplant by adulthood.Possible complications after the Kasai procedure include ascites,bacterial cholangitis, portal hypertension, and pruritis.

Post Liver Transplantation Biliary Atresia

If the atresia is complete, liver transplantation is the only option.Although liver transplantation is generally successful at treatingbiliary atresia, liver transplantation may have complications such asorgan rejection. Also, a donor liver may not become available. Further,in some patients, liver transplantation may not be successful at curingbiliary atresia.

Xanthoma

Xanthoma is a skin condition associated cholestatic liver diseases, inwhich certain fats build up under the surface of the skin. Cholestasisresults in several disturbances of lipid metabolism resulting information of an abnormal lipid particle in the blood called lipoproteinX. Lipoprotein X is formed by regurgitation of bile lipids into theblood from the liver and does not bind to the LDL receptor to delivercholesterol to cells throughout the body as does normal LDL. LipoproteinX increases liver cholesterol production by five fold and blocks normalremoval of lipoprotein particles from the blood by the liver.

Compounds

In some embodiments, provided herein are ASBT inhibitors that reduce orinhibit bile acid recycling in the distal gastrointestinal (GI) tract,including the distal ileum, the colon and/or the rectum. In certainembodiments, the ASBTIs are systemically absorbed. In certainembodiments, the ASBTIs are not systemically absorbed. In someembodiments, ASBTIs described herein are modified or substituted (e.g.,with a -L-K group) to be non-systemic. In certain embodiments, any ASBTinhibitor is modified or substituted with one or more charged groups(e.g., K) and optionally, one or more linker (e.g., L), wherein L and Kare as defined herein.

In some embodiments, an ASBTI suitable for the methods described hereinis a compound of Formula I:

wherein:R¹ is a straight chained C₁₋₆ alkyl group;R² is a straight chained C₁₋₆ alkyl group;R³ is hydrogen or a group OR¹¹ in which R¹¹ is hydrogen, optionallysubstituted C₁₋₆ alkyl or a C₁₋₄ alkylcarbonyl group;R⁴ is pyridyl or optionally substituted phenyl or -L-K₁; wherein z is 1,2 or 3; each L is independently a substituted or unsubstituted alkyl, asubstituted or unsubstituted heteroalkyl, a substituted or unsubstitutedalkoxy, a substituted or unsubstituted aminoalkyl group, a substitutedor unsubstituted aryl, a substituted or unsubstituted heteroaryl, asubstituted or unsubstituted cycloalkyl, or a substituted orunsubstituted heterocycloalkyl; each K is a moiety that preventssystemic absorption;R⁵, R⁶, R⁷ and R⁸ are the same or different and each is selected fromhydrogen, halogen, cyano, R⁵-acetylide, OR¹⁵, optionally substitutedC₁₋₆ alkyl, COR¹⁵, CH(OH)R¹⁵, S(O)_(n)R¹⁵, P(O)(OR¹⁵)₂, OCOR¹⁵, OCF3,OCN, SCN, NHCN, CH₂OR¹⁵, CHO, (CH₂)_(p)CN, CONR¹²R¹³, (CH₂)_(p)CO₂R¹⁵,(CH₂)NR¹²R¹³, CO₂R¹⁵, NHCOCF₃, NHSO₂R¹⁵, OCH₂OR¹⁵, OCH═CHR¹⁵,O(CH₂CH₂O)R¹⁵, O(CH₂)_(p)SO₃R¹⁵, O(CH₂)_(p)NR¹²R¹³,O(CH₂)_(p)N⁺R¹²R¹³R¹⁴ and —W—R³¹, wherein W is O or NH and R³¹ isselected from

-   -   wherein p is an integer from 1-4, n is an integer from 0-3 and,        R¹², R¹³, R¹⁴ and R¹⁵ are independently selected from hydrogen        and optionally substituted C₁₋₆ alkyl; or        R⁶ and R⁷ are linked to form a group

-   -   wherein R¹² and R¹³ are as hereinbefore defined and m is 1 or 2;        and        R⁹ and R¹⁰ are the same or different and each is selected from        hydrogen or C₁₋₆ alkyl; and        salts, solvates and physiologically functional derivatives        thereof.

In some embodiments of the methods, the compound of Formula I is acompound

whereinR¹ is a straight chained C₁₋₆ alkyl group;R² is a straight chained C₁₋₆ alkyl group;R³ is hydrogen or a group OR¹¹ in which R¹¹ is hydrogen, optionallysubstituted C₁₋₆ alkyl or a C₁₋₆ alkylcarbonyl group;R⁴ is optionally substituted phenyl;R⁵, R⁶ and R⁸ are independently selected from hydrogen, C₁₋₄ alkyloptionally substituted by fluorine, C₁₋₄ alkoxy, halogen, or hydroxy;R⁷ is selected from halogen, cyano, R¹⁵-acetylide, OR¹⁵, optionallysubstituted C₁₋₆ alkyl, COR¹⁵, CH(OH)R¹⁵, S(O)_(n)R¹⁵, P(O)(OR¹⁵)₂,OCOR¹⁵, OCF₃, OCN, SCN, HNCN, CH₂OR¹⁵, CHO, (CH₂)_(p)CN, CONR¹²R¹³,(CH₂)_(p)CO₂R¹⁵, (CH₂)_(p)NR¹²R¹³, CO₂R¹⁵, NHCOCF₃, NHSO₂R¹⁵, OCH₂OR¹⁵,OCH═CHR¹⁵, O(CH₂CH₂O)R¹⁵, O(CH₂)_(p)SO₃R¹⁵, O(CH₂)NR¹²R¹³ andO(CH₂)_(p)N⁺R¹²R¹³R¹⁴;

-   -   wherein n, p and R¹² to R¹⁵ are as hereinbefore defined;        with the proviso that at least two of R⁵ to R⁸ are not hydrogen;        and        salts solvates and physiologically functional derivatives        thereof.

In some embodiments of the methods described herein, the compound ofFormula I is a compound

whereinR¹ is a straight chained C₁₋₆ alkyl group;R² is a straight chained C₁₋₆ alkyl group;R³ is hydrogen or a group OR¹¹ in which R¹¹ is hydrogen, optionallysubstituted C₁₋₆ alkyl or a C₁₋₆ alkylcarbonyl group;R⁴ is un-substituted phenyl;R⁵ is hydrogen or halogen;R⁶ and R⁸ are independently selected from hydrogen, C₁₋₄ alkyloptionally substituted by fluorine, C₁₋₄ alkoxy, halogen, or hydroxy;R⁷ is selected from OR¹⁵, S(O)_(n)R¹⁵, OCOR¹⁵, OCF₃, OCN, SCN, CHO,OCH₂OR¹⁵, OCH═CHR¹⁵, O(CH₂CH₂O)nR¹⁵, O(CH₂)_(p)SO₃R¹⁵, O(CH₂)_(p)NR¹²R¹³and O(CH₂)_(p)N⁺R¹²R¹³R¹⁴ wherein p is an integer from 1-4, n is aninteger from 0-3, and R¹², R¹³, R¹⁴, and R¹⁵ are independently selectedfrom hydrogen and optionally substituted C₁₋₆ alkyl;R⁹ and R¹⁰ are the same or different and each is selected from hydrogenor C₁₋₆ alkyl; andsalts, solvates and physiologically functional derivatives thereof.

In some embodiments of the methods, wherein the compound of Formula I isa compound

whereinR¹ is methyl, ethyl or n-propyl;R² is methyl, ethyl, n-propyl, n-butyl or n-pentyl;R³ is hydrogen or a group OR¹¹ in which R¹¹ is hydrogen, optionallysubstituted C₁₋₆ alkyl or a C₁₋₆ alkylcarbonyl group;R⁴ is un-substituted phenyl;R⁵ is hydrogen;R⁶ and R⁸ are independently selected from hydrogen, C₁₋₄ alkyloptionally substituted by fluorine, C₁₋₄ alkoxy, halogen, or hydroxy;R⁷ is selected from OR¹⁵, S(O)_(n)R¹⁵, OCOR¹⁵, OCF₃, OCN, SCN, CHO,OCH₂OR¹⁵, OCH═CHR¹⁵, O(CH₂CH₂O)nR⁵, O(CH₂)_(p)SO₃R¹⁵, O(CH₂)_(p)NR¹²R¹³and O(CH₂)_(p)N⁺R¹²R¹³R¹⁴ wherein p is an integer from 1-4, n is aninteger from 0-3, and R¹², R¹³, R¹⁴, and R¹⁵ are independently selectedfrom hydrogen and optionally substituted C₁₋₆ alkyl;R⁹ and R¹⁰ are the same or different and each is selected from hydrogenor C₁₋₆ alkyl; and salts, solvates and physiologically functionalderivatives thereof.

In some embodiments of the methods, the compound of Formula I is acompound wherein

R¹ is methyl, ethyl or n-propyl;R² is methyl, ethyl, n-propyl, n-butyl or n-pentyl;R³ is hydrogen or a group OR¹¹ in which R¹¹ is hydrogen, optionallysubstituted C₁₋₆ alkyl or a C₁₋₆ alkylcarbonyl group;R⁴ is un-substituted phenyl;R⁵ is hydrogen;R⁶ is C₁₋₄ alkoxy, halogen, or hydroxy;R⁷ is OR¹⁵, wherein R¹⁵ is hydrogen or optionally substituted C₁₋₆alkyl;R⁸ is hydrogen or halogen;R⁹ and R¹⁰ are the same or different and each is selected from hydrogenor C₁₋₆ alkyl; and salts, solvates and physiologically functionalderivatives thereof.

In some embodiments of the methods, the compound of Formula I is

-   (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine    1,1-dioxide;-   (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-4-ol    1,1-dioxide;-   (±)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine    1,1-dioxide;-   (±)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepin-4-ol    1,1-dioxide;-   (3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine    1,1-dioxide;-   (3R,5R)-7-Bromo-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benxothiaxepin-4-ol    1,1-dioxide;-   (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-7,8-diol    1,1-dioxide;-   (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepin-7-ol    1,1-dioxide;-   (3R,5R)-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol    1,1-dioxide;-   (±)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine    1,1-dioxide;-   (±)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol    1,1-dioxide;-   (±)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine-4,8-diol;-   (±)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-thiol    1,1-dioxide;-   (±)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-sulfonic    acid 1,1-dioxide;-   (±)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8,9-dimethoxy-5-phenyl-1,4-benzothiazepine    1,1-dioxide;-   (3R,5R)-3-butyl-7,8-diethoxy-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine    1,1-dioxide;-   (±)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine    1,1-dioxide;-   (±)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepine    1,1-dioxide hydrochloride;-   (±)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-carbaldehyde-1,1-dioxide;-   3,3-Diethyl-2,3,4,5-tetrahydro-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine    1,1-dioxide;-   3,3-Diethyl-2,3,4,5-tetrahydro-8-methoxy-5-phenyl-1,4-benzothiazepine    1,1-dioxide;-   3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazpin-4,8-diol    1,1-dioxide;-   (RS)-3,3-Diethyl-2,3,4,5-tetrahydro-4-hydroxy-7,8-dimethoxy-5-phenyl-1,4-benzothiazepine    1,1-dioxide;-   (±)-Trans-3-butyl-8-ethoxy-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4-ol-1-dioxide;-   (±)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-8-isopropoxy-5-phenyl-1,4-benzothiazepin-4-ol    1,1-dioxide;-   (±)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-7,8,9-timethoxy-5-phenyl-1,4-benzothiazepin-4-ol    1,1-dioxide;-   (3R,5R)-3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-4,7,8-triol    1,1-dioxide;-   (±)-Trans-3-butyl-3-ethyl-2,3,4,5-tetrahydro-4,7,8-timethoxy-5-phenyl-1,4-benzothiazepine    1,1-dioxide;-   3,3-Diethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol    1,1-dioxide;-   3,3-Diethyl-2,3,4,5-tetrahydro-7-methoxy-5-phenyl-1,4-benzothiazepin-8-ol    1,1-dioxide;-   3,3 Dibutyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepin-8-ol    1,1-dioxide;-   (±)-Trans-3-Butyl-3-ethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl    hydrogen sulfate;-   or-   3,3-Diethyl-2,3,4,5-tetrahydro-1,1-dioxo-5-phenyl-1,4-benzothiazepin-8-yl    hydrogen sulfate.

In some embodiments, the compound of Formula I is

In some embodiments of the methods, the compound of Formula I is

In some embodiments, the compound of Formula I is not a structure shownas:

wherein m represents an integer of 1 or 2, and R³ and R⁴, which may bemutually different, each represents an alkyl group having 1 to 5 carbonatoms.

In some embodiments, an ASBTI suitable for the methods described hereinis a compound of Formula II

wherein:

-   -   q is an integer from 1 to 4;    -   n is an integer from 0 to 2;    -   R¹ and R² are independently selected from the group consisting        of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl,        alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl,        and cycloalkyl,    -   wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl,        arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio,        (polyalkyl)aryl, and cycloalkyl optionally are substituted with        one or more substituents selected from the group consisting of        OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹R¹⁰A⁻, P⁺R⁹R¹⁰R¹¹A⁻,        S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰,    -   wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,        (polyalkyl)aryl, and cycloalkyl optionally have one or more        carbons replaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻,        P⁺R⁹R¹⁰A⁻, or phenylene,    -   wherein R⁹, R¹⁰, and R^(w) are independently selected from the        group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl,        aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and        alkylammoniumalkyl; or    -   R¹ and R² taken together with the carbon to which they are        attached form C₃-C₁₀ cycloalkyl;    -   R³ and R⁴ are independently selected from the group consisting        of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR⁹,        NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein R⁹ and R¹⁰ are as        defined above; or    -   R³ and R⁴ together ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or ═CR¹¹R¹²,    -   wherein R¹¹ and R¹² are independently selected from the group        consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl,        alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl,        carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹,        S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰,        wherein R⁹ and R¹⁰ are as defined above, provided that both R³        and R⁴ cannot be OH, NH₂, and SH, or    -   R¹¹ and R¹² together with the nitrogen or carbon atom to which        they are attached form a cyclic ring;    -   R⁵ and R⁶ are independently selected from the group consisting        of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,        quaternary heterocycle, quaternary heteroaryl, OR⁹, SR⁹, S(O)R⁹,        SO₂R⁹, SO₃R⁹, and -L_(z)-K_(z);    -   wherein z is 1, 2 or 3; each L is independently a substituted or        unsubstituted alkyl, a substituted or unsubstituted heteroalkyl,        a substituted or unsubstituted alkoxy, a substituted or        unsubstituted aminoalkyl group, a substituted or unsubstituted        aryl, a substituted or unsubstituted heteroaryl, a substituted        or unsubstituted cycloalkyl, or a substituted or unsubstituted        heterocycloalkyl; each K is a moiety that prevents systemic        absorption;    -   wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,        quaternary heterocycle, and quaternary heteroaryl can be        substituted with one or more substituent groups independently        selected from the group consisting of alkyl, alkenyl, alkynyl,        polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,        arylalkyl, quaternary heterocycle, quaternary heteroaryl,        halogen, oxo, R¹⁵, OR¹³, OR¹³R¹⁴, NR¹³R¹⁴, SR¹³, S(O)R¹³,        SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM,        SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, CR¹³, P(O)R¹³R¹⁴,        P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻        wherein:    -   A⁻ is a pharmaceutically acceptable anion and M is a        pharmaceutically acceptable cation, said alkyl, alkenyl,        alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and        heterocycle can be further substituted with one or more        substituent groups selected from the group consisting of OR⁷,        NR⁷R⁸, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸,        N⁺R⁷R⁸R⁹A⁻, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,        heterocycle, arylalkyl, quaternary heterocycle, quaternary        heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷) OR⁸ and    -   wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,        aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have        one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A⁻, S, SO, SO₂,        S⁺R⁷A⁻, PR⁷, P(O)R⁷, P⁺R⁷R⁸A⁻, or phenylene, and R¹³, R¹⁴, and        R¹⁵ are independently selected from the group consisting of        hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl,        cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle,        quaternary hetetoaryl, quarterly heteroarylalkyl, and -G-T-V-W,    -   wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and        polyalkyl optionally have one or more carbons replaced by O,        NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, PR, P⁺R⁹R¹⁰A⁻, P(O)R⁹,        phenylene, carbohydrate, C₂-C₇ polyol, amino acid, peptide, or        polypeptide, and    -   G, T and V are each independently a bond, —O—, —S—, —N(H)—,        substituted or unsubstituted alkyl, —O-alkyl, —N(H)-alkyl,        —C(O)N(H)—, —N(H)C(O)—, —N(H)C(O)N(H)—, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted aryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted alkenylalkyl,        alkynylalkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted heterocycle, substituted or        unsubstituted carboxyalkyl, substituted or unsubstituted        carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl,        and    -   W is quaternary heterocycle, quaternary heteroaryl, quaternary        heteroarylalkyl, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹⁰R¹¹A⁻, OS(O)₂OM, or        S⁺R⁹R¹⁰A⁻, and    -   R¹³, R¹⁴ and R¹⁵ are optionally substituted with one or more        groups selected from the group consisting of sulfoalkyl,        quaternary heterocycle, quaternary heteroaryl, OR⁹, NR⁹R¹⁰,        N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O) R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN,        halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A⁻,        S⁺R⁹R¹⁰A⁻, and C(O)OM,    -   wherein R¹⁶ and R¹⁷ are independently selected from the        substituents constituting R⁹ and M; or    -   R¹⁴ and R¹⁵, together with the nitrogen atom to which they are        attached, form a cyclic ring; and is selected from the group        consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,        heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl;        and    -   R⁷ and R⁸ are independently selected from the group consisting        of hydrogen and alkyl; and    -   one or more R^(x) are independently selected from the group        consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy,        aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle,        heteroaryl, polyether, quaternary heterocycle, quaternary        heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, S(O)₂R¹³, SO₃R¹³,        S⁺R¹³R¹⁴A⁻, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM,        SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR¹⁴C(O)R³, C(O)OM, COR¹³,        OR¹⁸, S(O)_(n) NR¹⁸, NR¹³R¹⁸, NR¹⁸R¹⁴, N⁺R⁹R¹¹R¹²A⁻,        P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide, and        carbohydrate,    -   wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl,        heterocycle, acyloxy, arylalkyl, haloalkyl, polyether,        quaternary heterocycle, and quaternary heteroaryl can be further        substituted with OR⁹, NR⁹R¹⁰, NR⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹,        SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰,        PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)M, and    -   wherein R¹⁸ is selected from the group consisting of acyl,        arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,    -   wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle,        heteroaryl, alkyl, quaternary heterocycle, and quaternary        heteroaryl optionally are substituted with one or more        substituents selected from the group consisting of OR⁹, NR⁹R¹⁰,        NR⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₃R⁹, CN, halogen,        CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, and C(O)OM,    -   wherein in R^(x), one or more carbons are optionally replaced by        O, NR¹³, N⁺R¹³R¹⁴A⁻, SO, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R¹³,        P⁺R¹³R¹⁴A⁻, phenylene, amino acid, peptide, polypeptide,        carbohydrate, polyether, or polyalkyl,    -   wherein in said polyalkyl, phenylene, amino acid, peptide,        polypeptide, and carbohydrate, one or more carbons are        optionally replaced by O, NR⁹, R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻,        P⁺R⁹, P⁺R⁹R¹⁰A⁻, or P(O)R⁹;    -   wherein quaternary heterocycle and quaternary heteroaryl are        optionally substituted with one or more groups selected from the        group consisting of alkyl, alkenyl, alkynyl, polyalkyl,        polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl,        halogen, oxo, OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³,        NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,        C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻,        P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,    -   provided that both R⁵ and R⁶ cannot be hydrogen or SH;    -   provided that when R⁵ or R⁶ is phenyl, only one of R¹ or R² is        H;        provided that when q=1 and R^(x) is styryl, anilido, or        anilinocarbonyl, only one of R⁵ or R⁶ is alkyl; or a        pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments of the methods, the compound of Formula II is acompound wherein

-   -   q is an integer from 1 to 4;    -   n is 2;    -   R¹ and R² are independently selected from the group consisting        of H, alkyl, alkoxy, dialkylamino, and alkylthio,    -   wherein alkyl, alkoxy, dialkylamino, and alkylthio are        optionally substituted with one or more substituents selected        from the group consisting of OR⁹, NR⁹R¹⁰, SR⁹, SO₂R⁹, CO₂R⁹, CN,        halogen, oxo, and CONR⁹R¹⁰;    -   each R⁹ and R¹⁰ are each independently selected from the group        consisting of H, alkyl, cycloalkyl, aryl, acyl, heterocycle, and        arylalkyl;    -   R³ and R⁴ are independently selected from the group consisting        of H, alkyl, acyloxy, OR⁹, NR⁹R¹⁰, SR⁹, and SO₂R⁹, wherein R⁹        and R¹⁰ are as defined above;    -   R¹¹ and R¹² are independently selected from the group consisting        of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,        alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl,        cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹,        CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as        defined above, provided that both R³ and R⁴ cannot be OH, NH₂,        and SH, or    -   R¹¹ and R¹² together with the nitrogen or carbon atom to which        they are attached form a cyclic ring;    -   R⁵ and R⁶ are independently selected from the group consisting        of H, alkyl, aryl, cycloalkyl, heterocycle, and -L_(z)-K_(z);    -   wherein z is 1 or 2; each L is independently a substituted or        unsubstituted alkyl, a substituted or unsubstituted heteroalkyl,        a substituted or unsubstituted aryl, a substituted or        unsubstituted heteroaryl, a substituted or unsubstituted        cycloalkyl, or a substituted or unsubstituted heterocycloalkyl;        each K is a moiety that prevents systemic absorption;    -   wherein alkyl, aryl, cycloalkyl, and heterocycle can be        substituted with one or more substituent groups independently        selected from the group consisting of alkyl, aryl, haloalkyl,        cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle,        quaternary heteroaryl, halogen, oxo, OR¹³, OR¹³R¹⁴, NR¹³R¹⁴,        SR¹³, SO₂R¹³, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, and CR¹³,    -   wherein:    -   A⁻ is a pharmaceutically acceptable anion and M is a        pharmaceutically acceptable cation;    -   R¹³, R¹⁴, and R¹⁵ are independently selected from the group        consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl,        aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary        heterocycle, quaternary heteroaryl, and quaternary        heteroarylalkyl, wherein R¹³, R¹⁴ and R¹⁵ are optionally        substituted with one or more groups selected from the group        consisting of quaternary heterocycle, quaternary heteroaryl,        OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O) R⁹, SO₂R⁹, SO₃R⁹, oxo,        CO₂R⁹, CN, halogen, and CONR⁹R¹⁰; or    -   R¹⁴ and R¹⁵, together with the nitrogen atom to which they are        attached, form a cyclic ring; and is selected from the group        consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,        heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl;        and    -   R⁷ and R⁸ are independently selected from the group consisting        of hydrogen and alkyl; and    -   one or more R^(x) are independently selected from the group        consisting of H, alkyl, acyloxy, aryl, arylalkyl, halogen,        haloalkyl, cycloalkyl, heterocycle, heteroaryl, OR¹³, NR¹³R¹⁴,        SR¹³, S(O)₂R¹³, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, SO₂NR¹³R¹⁴,        NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴, NR¹⁴C(O)R¹³, and COR¹³;        provided that both R⁵ and R⁶ cannot be hydrogen;        provided that when R⁵ or R⁶ is phenyl, only one of R¹ or R² is        H;        provided that when q=1 and R^(x) is styryl, anilido, or        anilinocarbonyl, only one of R⁵ or R⁶ is alkyl; or a        pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments, the compound of Formula II is a compound wherein

-   -   q is 1;    -   n is 2;    -   R^(x) is N(CH₃)₂;    -   R⁷ and R⁸ are independently H;    -   R¹ and R² is alkyl;    -   R³ is H, and R⁴ is OH;    -   R⁵ is H, and R⁶ is selected from the group consisting of alkyl,        alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary        heterocycle, quaternary heteroaryl, OR⁹, SR⁹, S(O)R⁹, SO₂R⁹,        SO₃R⁹, and -L_(z)-K_(z);    -   wherein z is 1, 2 or 3; each L is independently a substituted or        unsubstituted alkyl, a substituted or unsubstituted heteroalkyl,        a substituted or unsubstituted alkoxy, a substituted or        unsubstituted aminoalkyl group, a substituted or unsubstituted        aryl, a substituted or unsubstituted heteroaryl, a substituted        or unsubstituted cycloalkyl, or a substituted or unsubstituted        heterocycloalkyl; each K is a moiety that prevents systemic        absorption;    -   wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,        quaternary heterocycle, and quaternary heteroaryl can be        substituted with one or more substituent groups independently        selected from the group consisting of alkyl, alkenyl, alkynyl,        polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle,        arylalkyl, quaternary heterocycle, quaternary heteroaryl,        halogen, oxo, R¹⁵, OR¹³, OR¹³R¹⁴, NR¹³R¹⁴, SR¹³, S(O)R¹³,        SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM,        SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, CR¹³, P(O)R¹³R¹⁴,        P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,    -   wherein A⁻ is a pharmaceutically acceptable anion and M is a        pharmaceutically acceptable cation, said alkyl, alkenyl,        alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and        heterocycle can be further substituted with one or more        substituent groups selected from the group consisting of OR⁷,        NR⁷R⁸, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸,        N⁺R⁷R⁸R⁹A⁻, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,        heterocycle, arylalkyl, quaternary heterocycle, quaternary        heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷) OR⁸ and    -   wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,        aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have        one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A⁻, S, SO, SO₂,        S⁺R⁷A⁻, PR⁷, P(O)R⁷, P⁺R⁷R⁸A⁻, or phenylene, and R¹³, R¹⁴, and        R¹⁵ are independently selected from the group consisting of        hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl,        cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle,        quaternary hetetoaryl, quaternary heteroarylalkyl, and -G-T-V-W,    -   wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and        polyalkyl optionally have one or more carbons replaced by O,        NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, PR, P⁺R⁹R¹⁰A⁻, P(O)R⁹,        phenylene, carbohydrate, C₂-C₇ polyol, amino acid, peptide, or        polypeptide, and    -   G, T and V are each independently a bond, —O—, —S—, —N(H)—,        substituted or unsubstituted alkyl, —O-alkyl, —N(H)-alkyl,        —C(O)N(H)—, —N(H)C(O)—, —N(H)C(O)N(H)—, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted aryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted alkenylalkyl,        alkynylalkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted heterocycle, substituted or        unsubstituted carboxyalkyl, substituted or unsubstituted        carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl,        and    -   W is quaternary heterocycle, quaternary heteroaryl, quaternary        heteroarylalkyl, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹⁰R¹¹A⁻, OS(O)₂OM, or        S⁺R⁹R¹⁰A⁻, and    -   R⁹ and R¹⁰ are independently selected from the group consisting        of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,        heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl;    -   R¹¹ and R¹² are independently selected from the group consisting        of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,        alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl,        cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹,        CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as        defined above, provided that both R³ and R⁴ cannot be OH, NH₂,        and SH, or    -   R¹¹ and R¹² together with the nitrogen or carbon atom to which        they are attached form a cyclic ring;    -   R¹³, R¹⁴ and R¹⁵ are optionally substituted with one or more        groups selected from the group consisting of sulfoalkyl,        quaternary heterocycle, quaternary heteroaryl, OR⁹, NR⁹R¹⁰,        N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O) R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen,        CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A⁻,        S⁺R⁹R¹⁰A⁻, and C(O)OM,    -   wherein R¹⁶ and R¹⁷ are independently selected from the        substituents constituting R⁹ and M; or    -   R¹⁴ and R¹⁵, together with the nitrogen atom to which they are        attached, form a cyclic ring; and is selected from the group        consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,        heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl;    -   or a pharmaceutically acceptable salt, solvate, or prodrug        thereof.

In some embodiments, the compound of Formula II is a compound wherein

-   -   q is 1;    -   n is 2;    -   R^(x) is N(CH₃)₂;    -   R⁷ and R⁸ are independently H;    -   R¹ and R² is independently C₁-C₄ alkyl;    -   R³ is H, and R⁴ is OH;    -   R⁵ is H, and R⁶ is aryl substituted with one or more substituent        groups independently selected from the group consisting of        alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,        cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle,        quaternary heteroaryl, halogen, oxo, R¹⁵, OR¹³, OR¹³R¹⁴,        NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵,        NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM,        CR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and        N⁺R⁹R¹¹R¹²A⁻,    -   wherein A⁻ is a pharmaceutically acceptable anion and M is a        pharmaceutically acceptable cation, said alkyl, alkenyl,        alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and        heterocycle can be further substituted with one or more        substituent groups selected from the group consisting of OR⁷,        NR⁷R⁸, S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸,        N⁺R⁷R⁸R⁹A⁻, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,        heterocycle, arylalkyl, quaternary heterocycle, quaternary        heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷) OR⁸ and    -   wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,        aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have        one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A⁻, S, SO, SO₂,        S⁺R⁷A⁻, PR⁷, P(O)R⁷, P⁺R⁷R⁸A⁻, or phenylene, and R¹³, R¹⁴, and        R¹⁵ are independently selected from the group consisting of        hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl,        cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle,        quaternary hetetoaryl, quaternary heteroarylalkyl, and -G-T-V-W,    -   wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and        polyalkyl optionally have one or more carbons replaced by O,        NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, PR, P⁺R⁹R¹⁰A⁻, P(O)R⁹,        phenylene, carbohydrate, C₂-C₇ polyol, amino acid, peptide, or        polypeptide, and    -   G, T and V are each independently a bond, —O—, —S—, —N(H)—,        substituted or unsubstituted alkyl, —O-alkyl, —N(H)-alkyl,        —C(O)N(H)—, —N(H)C(O)—, —N(H)C(O)N(H)—, substituted or        unsubstituted alkenyl, substituted or unsubstituted alkynyl,        substituted or unsubstituted aryl, substituted or unsubstituted        arylalkyl, substituted or unsubstituted alkenylalkyl,        alkynylalkyl, substituted or unsubstituted heteroalkyl,        substituted or unsubstituted heterocycle, substituted or        unsubstituted carboxyalkyl, substituted or unsubstituted        carboalkoxyalkyl, or substituted or unsubstituted cycloalkyl,        and    -   W is quaternary heterocycle, quaternary heteroaryl, quaternary        heteroarylalkyl, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹⁰R¹¹A⁻, OS(O)₂OM, or        S⁺R⁹R¹⁰A⁻, and    -   R⁹ and R¹⁰ are independently selected from the group consisting        of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,        heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl;    -   R¹¹ and R¹² are independently selected from the group consisting        of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,        alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl,        cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹,        CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as        defined above, provided that both R³ and R⁴ cannot be OH, NH₂,        and SH, or    -   R¹¹ and R¹² together with the nitrogen or carbon atom to which        they are attached form a cyclic ring;    -   R¹³, R¹⁴ and R¹⁵ are optionally substituted with one or more        groups selected from the group consisting of sulfoalkyl,        quaternary heterocycle, quaternary heteroaryl, OR⁹, NR⁹R¹⁰,        N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O) R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN,        halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A⁻,        S⁺R⁹R¹⁰A⁻, and C(O)OM,    -   wherein R¹⁶ and R¹⁷ are independently selected from the        substituents constituting R⁹ and M; or    -   R¹⁴ and R¹⁵, together with the nitrogen atom to which they are        attached, form a cyclic ring; and is selected from the group        consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,        heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl;    -   or a pharmaceutically acceptable salt, solvate, or prodrug        thereof.

In some embodiments of the methods, the compound of Formula II is acompound wherein

R⁵ and R⁶ are independently selected from the group consisting of H,aryl, heterocycle, quaternary heterocycle, and quaternary heteroaryl

-   -   wherein the aryl, heteroaryl, quaternary heterocycle and        quaternary heteroaryl are optionally substituted with one or        more groups selected from the group consisting of alkyl,        alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,        cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³, OR¹³R¹⁴,        NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵,        NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM,        COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻,        N⁺R⁹R¹¹R¹²A⁻ and -L_(z)-K_(z).

In some embodiments of the methods, the compound of Formula II is acompound wherein

R⁵ or R⁶ is —Ar—(R^(y))_(t),

-   -   t is an integer from 0 to 5;    -   Ar is selected from the group consisting of phenyl, thiophenyl,        pyridyl, piperazinyl, piperonyl, pyrrolyl, naphthyl, furanyl,        anthracenyl, quinolinyl, isoquinolinyl, quinoxalinyl,        imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrimidinyl,        thiazolyl, triazolyl, isothiazolyl, indolyl, benzoimidazolyl,        benzoxazolyl, benzothiazolyl, and benzoisothiazolyl; and    -   one or more R^(y) are independently selected from the group        consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether,        aryl, halo alkyl, cycloalkyl, heterocycle, arylalkyl, halogen,        oxo, OR¹³, OR¹³R¹⁴, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³,        NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,        C(O)NR¹³R¹⁴, C(O)OM, COR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻,        P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, N⁺R⁹R¹¹R¹²A⁻ and -L_(z)-K_(z);    -   wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,        aryl, haloalkyl, cycloalkyl, and heterocycle can be further        substituted with one or more substituent groups selected from        the group consisting of OR¹³, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³,        SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, oxo, CONR⁷R⁸,        N⁺R⁷R⁸R⁹A⁻, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,        heterocycle, arylalkyl, quaternary heterocycle, quaternary        heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸A⁻, and P(O)(OR⁷)OR⁸, and or        phenylene;    -   wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,        aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have        one or more carbons replaced by O, NR⁷, N⁺R⁷R⁸A⁻, S, SO, SO₂,        S⁺R⁷A⁻, PR⁷, P(O)R⁷, P⁺R⁷R⁸A⁻, or phenylene.

In some embodiments of the methods, the compound of Formula II is acompound wherein R⁵ or R⁶ is

In some embodiments of the methods, the compound of Formula II is acompound wherein n is 1 or 2. In some embodiments of the methods, thecompound of Formula II is a compound wherein R¹ and R² are independentlyH or C₁₋₇ alkyl. In some embodiments of the methods, the compound ofFormula II is a compound wherein each C₁₋₇ alkyl is independently ethyl,n-propyl, n-butyl, or isobutyl. In some embodiments of the methods, thecompound of Formula II is a compound wherein R³ and R⁴ are independentlyH or OR⁹. In some embodiments of the methods, compound of Formula II isa compound wherein R⁹ is H

In some embodiments of the methods, the compound of Formula II is acompound wherein one or more R^(x) are in the 7-, 8- or 9-position ofthe benzo ring of Formula II. In some embodiments of the methods, thecompound of Formula II is a compound wherein R^(x) is in the 7-positionof the benzo ring of Formula II. In some embodiments of the methods, thecompound of Formula II is a compound wherein one or more R^(x) areindependently selected from OR¹³ and NR¹³R¹⁴.

In some embodiments of the methods, the compound of Formula II is acompound wherein:

q is 1 or 2;n is 2;R¹ and R² are each alkyl;R³ is hydroxy;R⁴ and R⁶ are hydrogen;R⁵ has the formulawherein

t is an integer from 0 to 5;

-   -   one or more R^(y) are OR¹³ or OR¹³R¹⁴    -   R¹³ and R¹⁴ are independently selected from the group consisting        of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl,        arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary        heterocycle, quaternary heteroaryl, and quaternary        heteroarylalkyl;    -   wherein said alkyl, alkenyl, alkynyl, arylalkyl, heterocycle,        and polyalkyl groups optionally have one or more carbons        replaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, PR⁹,        P⁺R⁹R¹⁰A⁻, P(O)R⁹, phenylene, carbohydrate, amino acid, peptide,        or polypeptide;    -   R¹³ and R¹⁴ are optionally substituted with one or more groups        independently selected from the group consisting of sulfoalkyl,        quaternary heterocycle, quaternary heteroaryl, OR⁹, NR⁹R¹⁰,        N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN,        halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR⁷, P⁺R⁹R¹⁰R¹¹A⁻,        S⁺R⁹R¹⁰A⁻, and C(O)OM,    -   wherein A is a pharmaceutically acceptable anion, and M is a        pharmaceutically acceptable cation,    -   R⁹ and R¹⁰ are independently selected from the group consisting        of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl,        heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl;    -   R¹¹ and R¹² are independently selected from the group consisting        of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,        alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl,        cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹,        CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as        defined above, provided that both R³ and R⁴ cannot be OH, NH₂,        and SH; or    -   R¹¹ and R¹² together with the nitrogen or carbon atom to which        they are attached form a cyclic ring; and    -   R¹⁶ and R¹⁷ are independently selected from the substituents        constituting R⁹ and M;    -   R⁷ and R⁸ are hydrogen; and    -   one or more R^(x) are independently selected from the group        consisting of alkoxy, alkylamino and dialkylamino and —W—R³¹,        wherein W is O or NH and R³¹ is selected from

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

In some embodiments, a compound of Formula II is

or the like.

In some embodiments of the methods, the compound of Formula II is

In certain embodiments, ASBTIs suitable for the methods described hereinare non-systemic analogs of Compound 100C. Certain compounds providedherein are Compound 100C analogues modified or substituted to comprise acharged group. In specific embodiments, the Compound 100C analogues aremodified or substituted with a charged group that is an ammonium group(e.g., a cyclic ar acyclic ammonium group). In certain embodiments, theammonium group is a non-protic ammonium group that contains a quaternarynitrogen.

In some embodiments, a compound of Formula II is

In some embodiments, a compound of Formula II is1-[[5-[[3-[(3S,4R,5R)-3-butyl-7-(dimethylamino)-3-ethyl-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5yl]phenyl]amino]-5-oxopentyl]amino]-1-deoxy-D-glucitolor SA HMR1741 (a.k.a. BARI-1741).

In some embodiments, a compound of Formula II is

In some embodiments, a compound of Formula II ispotassium((2R,3R,4S,5R,6R)-4-benzyloxy-6-{3-[3-((3S,4R,5R)-3-butyl-7-dimethylamino-3-ethyl-4-hydroxy-1,1-dioxo-2,3,4,5-tetrahydro-1H-benzo[b]thiepin-5-yl)-phenyl]-ureido}-3,5-dihydroxy-tetrahydro-pyran-2-ylmethyl)sulphateethanolate, hydrate or SAR548304B (a.k.a. SAR-548304).

In some embodiments, an ASBTI suitable for the methods described hereinis a compound of Formula III:

-   -   wherein:        -   each R¹, R² is independently H, hydroxy, alkyl, alkoxy,            —C(═X)YR⁸, —YC(═X)R⁸, substituted or unsubstituted alkyl,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted aryl, substituted or unsubstituted alkyl-aryl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted alkyl-cycloalkyl, substituted or unsubstituted            heteroaryl, substituted or unsubstituted alkyl-heteroaryl,            substituted or unsubstituted heterocycloalkyl, substituted            or unsubstituted alkyl-heterocycloalkyl, or -L-K; or R¹ and            R² together with the nitrogen to which they are attached            form a 3-8-membered ring that is optionally substituted with            R⁸;        -   each R³, R⁴ is independently H, hydroxy, alkyl, alkoxy,            —C(═X)YR⁸, —YC(═X)R⁸, substituted or unsubstituted alkyl,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted aryl, substituted or unsubstituted alkyl-aryl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted alkyl-cycloalkyl, substituted or unsubstituted            heteroaryl, substituted or unsubstituted alkyl-heteroaryl,            substituted or unsubstituted heterocycloalkyl, substituted            or unsubstituted alkyl-heterocycloalkyl, or -L-K;        -   R⁵ is H, hydroxy, alkyl, alkoxy, —C(═X)YR⁸, —YC(═X)R⁸,            substituted or unsubstituted alkyl, substituted or            unsubstituted heteroalkyl, substituted or unsubstituted            aryl, substituted or unsubstituted alkyl-aryl, substituted            or unsubstituted cycloalkyl, substituted or unsubstituted            alkyl-cycloalkyl, substituted or unsubstituted heteroaryl,            substituted or unsubstituted alkyl-heteroaryl, substituted            or unsubstituted heterocycloalkyl, substituted or            unsubstituted alkyl-heterocycloalkyl,        -   each R⁶, R⁷ is independently H, hydroxy, alkyl, alkoxy,            —C(═X)YR⁸, —YC(═X)R⁸, substituted or unsubstituted alkyl,            substituted or unsubstituted heteroalkyl, substituted or            unsubstituted aryl, substituted or unsubstituted alkyl-aryl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted alkyl-cycloalkyl, substituted or unsubstituted            heteroaryl, substituted or unsubstituted alkyl-heteroaryl,            substituted or unsubstituted heterocycloalkyl, substituted            or unsubstituted alkyl-heterocycloalkyl, or -L-K; or R⁶ and            R⁷ taken together form a bond;        -   each X is independently NH, S, or O;        -   each Y is independently NH, S, or O;        -   R⁸ is substituted or unsubstituted alkyl, substituted or            unsubstituted heteroalkyl, substituted or unsubstituted            aryl, substituted or unsubstituted alkyl-aryl, substituted            or unsubstituted cycloalkyl, substituted or unsubstituted            alkyl-cycloalkyl, substituted or unsubstituted heteroaryl,            substituted or unsubstituted alkyl-heteroaryl, substituted            or unsubstituted heterocycloalkyl, substituted or            unsubstituted alkyl-heterocycloalkyl, or -L-K;        -   L is A_(n), wherein            -   each A is independently NR¹, S(O)_(m), O, C(═X)Y,                Y(C═X), substituted or unsubstituted alkyl, substituted                or unsubstituted heteroalkyl, substituted or                unsubstituted aryl, substituted or unsubstituted                heteroaryl, substituted or unsubstituted cycloalkyl, or                substituted or unsubstituted heterocycloalkyl; wherein                each m is independently 0-2;            -   n is 0-7;        -   K is a moiety that prevents systemic absorption;        -   provided that at least one of R¹, R², R³ or R⁴ is -L-K;    -   or a pharmaceutically acceptable prodrug thereof.

In some embodiments of a compound of Formula III, R¹ and R³ are -L-K. Insome embodiments, R¹, R² and R³ are -L-K.

In some embodiments, at least one of R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ is H.In certain embodiments, R⁵, R⁶, R⁷ are H and R¹, R², R³ and R⁴ arealkyl, aryl, alkyl-aryl, or heteroalkyl. In some embodiments, R¹ and R²are H. In some embodiments, R¹, R², R⁵, R⁶ and R⁷ are H. In someembodiments, R⁶ and R⁷ together form a bond. In certain embodiments, R⁵,R⁶ and R⁷ are H, alkyl or O-alkyl.

In some embodiments, R¹ and R³ are -L-K. In some embodiments, R¹, R² andR³ are -L-K. In some embodiments, R³ and R⁴ are -L-K. In someembodiments, R¹ and R² together with the nitrogen to which they areattached form a 3-8 membered ring and the ring is substituted with -L-K.In some embodiments, R¹ or R² or R³ or R⁴ are aryl optionallysubstituted with -L-K. In some embodiments, R¹ or R² or R³ or R⁴ arealkyl optionally substituted with -L-K. In some embodiments, R¹ or R² orR³ or R⁴ are alky-aryl optionally substituted with -L-K. In someembodiments, R¹ or R² or R³ or R⁴ are heteroalkyl optionally substitutedwith -L-K.

In some embodiments, L is a C₁-C₇alkyl. In some embodiments, L isheteroalkyl. In certain embodiments, L is C₁-C₇alkyl-aryl. In someembodiments, L is C₁-C₇alkyl-aryl-C₁-C₇alkyl.

In certain embodiments, K is a non-protic charged group. In somespecific embodiments, each K is a ammonium group. In some embodiments,each K is a cyclic non-protic ammonium group. In some embodiments, eachK is an acyclic non-protic ammonium group.

In certain embodiments, each K is a cyclic non-protic ammonium group ofstructure:

In certain embodiments, K is an acyclic non-protic ammonium group ofstructure:

-   -   wherein p, q, R⁹, R¹⁰ and Z are as defined above. In certain        embodiments, p is 1. In other embodiments, p is 2. In further        embodiments, p is 3. In some embodiments, q is 0. In other        embodiments, q is 1. In some other embodiments, q is 2.

The compounds further comprise 1, 2, 3 or 4 anionic counterions selectedfrom Cl⁻, Br⁻, I⁻, R¹¹SO₃ ⁻, (SO₃ ⁻—R¹¹—SO₃ ⁻), R¹¹CO₂ ⁻, (CO₂ ⁻—R¹¹—CO₂⁻), (R¹¹)₂(P═O)O⁻ and (R¹¹)(P═O)O₂ ²⁻ wherein R¹¹ is as defined above.In some embodiments, the counterion is Cl⁻, Br⁻, I⁻, CH₂CO₂ ⁻, CH₃SO₃ ⁻,or C₆H₅SO₃ ⁻ or CO₂ ⁻— (CH₂)₂—CO₂ ⁻. In some embodiments, the compoundof Formula III has one K group and one counterion. In other embodiments,the compound of Formula III has one K group, and two molecules of thecompound of Formula III have one counterion. In yet other embodiments,the compound of Formula III has two K groups and two counterions. Insome other embodiments, the compound of Formula III has one K groupcomprising two ammonium groups and two counterions.

Also described herein are compounds having the Formula IIIA:

wherein:

-   -   each R¹, R² is independently H, substituted or unsubstituted        alkyl, or -L-K; or R¹ and R² together with the nitrogen to which        they are attached form a 3-8-membered ring that is optionally        substituted with R⁸;    -   and R³, R⁴, R⁸, L and K are as defined above.

In some embodiments of compounds of Formula IIIA, L is A_(n), whereineach A is substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl, and n is 0-7. In certain specific embodimentsof the compound of Formula IIIA, R¹ is H. In some embodiments of FormulaIIIA, R¹ and R² together with the nitrogen to which they are attachedform a 3-8-membered ring that is optionally substituted with -L-K.

Also described herein are compounds having the Formula IIIB:

wherein:

-   -   each R³, R⁴ is independently H, substituted or unsubstituted        alkyl, substituted or unsubstituted heteroalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted alkyl-aryl, or        -L-K;    -   and R¹, R², L and K are as defined above.

In certain embodiments of Formula IIIB, R³ is H. In certain embodiments,R³ and R⁴ are each -L-K. In some embodiments, R³ is H and R⁴ issubstituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted alkyl-aryl containing one or two -L-K groups.

In some embodiments, an ASBTI suitable for the methods described hereinis a compound of Formula IIIC

wherein:

-   -   each R¹, R² is independently H, hydroxy, alkyl, alkoxy,        —C(═X)YR⁸, —YC(═X)R⁸, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted alkyl-aryl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted alkyl-cycloalkyl, substituted or unsubstituted        heteroaryl, substituted or unsubstituted alkyl-heteroaryl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted alkyl-heterocycloalkyl, or -L-K; or R¹ and R²        together with the nitrogen to which they are attached form a        3-8-membered ring that is optionally substituted with R⁸;    -   each R³, R⁴ is independently H, hydroxy, alkyl, alkoxy,        —C(═X)YR⁸, —YC(═X)R⁸, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted alkyl-aryl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted alkyl-cycloalkyl, substituted or unsubstituted        heteroaryl, substituted or unsubstituted alkyl-heteroaryl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted alkyl-heterocycloalkyl, or -L-K;    -   R⁵ is H, hydroxy, alkyl, alkoxy, —C(═X)YR⁸, —YC(═X)R⁸,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted aryl, substituted or        unsubstituted alkyl-aryl, substituted or unsubstituted        cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl,        substituted or unsubstituted heteroaryl, substituted or        unsubstituted alkyl-heteroaryl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted        alkyl-heterocycloalkyl,    -   each R⁶, R⁷ is independently H, hydroxy, alkyl, alkoxy,        —C(═X)YR⁸, —YC(═X)R⁸, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted alkyl-aryl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted alkyl-cycloalkyl, substituted or unsubstituted        heteroaryl, substituted or unsubstituted alkyl-heteroaryl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted alkyl-heterocycloalkyl, or -L-K; or R⁶ and R⁷        taken together form a bond;    -   each X is independently NH, S, or O;    -   each Y is independently NH, S, or O;    -   R⁸ is substituted or unsubstituted alkyl, substituted or        unsubstituted heteroalkyl, substituted or unsubstituted aryl,        substituted or unsubstituted alkyl-aryl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        alkyl-cycloalkyl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted alkyl-heteroaryl, substituted or        unsubstituted heterocycloalkyl, substituted or unsubstituted        alkyl-heterocycloalkyl, or -L-K;    -   L is A_(n), wherein        -   each A is independently NR¹, S(O)_(m), O, C(═X)Y, Y(C═X),            substituted or unsubstituted alkyl, substituted or            unsubstituted heteroalkyl, substituted or unsubstituted            aryl, substituted or unsubstituted heteroaryl, substituted            or unsubstituted cycloalkyl, or substituted or unsubstituted            heterocycloalkyl; wherein each m is independently 0-2;        -   n is 0-7;    -   K is a moiety that prevents systemic absorption;        or a pharmaceutically acceptable salt thereof.

In some specific embodiments of Formula I, II or III, K is selected from

In some embodiments, an ASBTI suitable for the methods described hereinis a compound of Formula IV:

wherein

R¹ is a straight chain C₁₋₆ alkyl group;

R² is a straight chain C₁₋₆ alkyl group;

R³ is hydrogen or a group OR¹¹ in which R¹¹ is hydrogen, optionallysubstituted C₁₋₆ alkyl or a C₁₋₆ alkylcarbonyl group;

R⁴ is pyridyl or an optionally substituted phenyl;

R⁵, R⁶ and R⁸ are the same or different and each is selected from:

-   -   hydrogen, halogen, cyano, R¹⁵-acetylide, OR¹⁵, optionally        substituted C₁₋₆ alkyl, COR¹⁵, CH(OH)R¹⁵, S(O)_(n)R¹⁵,        P(O)(OR¹⁵)₂, OCOR¹⁵, OCF₃, OCN, SCN, NHCN, CH₂OR¹⁵, CHO,        (CH₂)_(p)CN, CONR¹²R¹³, (CH₂)_(p)CO₂R¹⁵, (CH₂)_(p)NR¹²R¹³,        CO₂R¹⁵, NHCOCF₃, NHSO₂R¹⁵, OCH₂OR¹⁵, OCH═CHR¹⁵,        O(CH₂CH₂O)_(n)R¹⁵, O(CH₂)_(p)SO₃R¹⁵, O(CH₂)_(p)NR¹²R¹³ and        O(CH₂)_(p)N⁺R¹²R¹³R¹⁴ wherein

p is an integer from 1-4,

n is an integer from 0-3 and

R¹², R¹³, R¹⁴ and R¹⁵ are independently selected from hydrogen andoptionally substituted C¹⁻⁶ alkyl;

R⁷ is a group of the formula

-   -   wherein the hydroxyl groups may be substituted by acetyl,        benzyl,        -   or —(C₁-C₆)-alkyl-R¹⁷,    -   wherein the alkyl group may be substituted with one or more        hydroxyl groups;

R¹⁶ is —COOH, —CH₂—OH, —CH₂—O-Acetyl, —COOMe or —COOEt;

R¹⁷ is H, —OH, —NH₂, —COOH or COOR¹⁸;

R¹⁸ is (C₁-C₄)-alkyl or —NH—(C₁-C₄)-alkyl;

X is —NH— or —O—; and

R⁹ and R¹⁰ are the same or different and each is hydrogen or C₁-C₆alkyl; and salts thereof.

In some embodiments, a compound of Formula IV has the structure ofFormula IVA or Formula IVB:

In some embodiments, a compound of Formula IV has the structure ofFormula IVC:

In some embodiments of Formula IV, X is O and R⁷ is selected from

In some embodiments, a compound of Formula IV is:

In some embodiments, an ASBTI suitable for the methods described hereinis a compound of Formula V:

wherein:

R^(v) is selected from hydrogen or C₁₋₆alkyl;

One of R¹ and R² are selected from hydrogen or C₁₋₆alkyl and the otheris selected from C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen, hydroxy,amino, mercapto, C₁₋₆alkyl, C₁₋₆alkoxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆-alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl;

n is 0-5;

one of R⁴ and R⁵ is a group of formula (VA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl;

-   -   wherein R³ and R⁶ and the other of R⁴ and R⁵ may be optionally        substituted on carbon by one or more R¹⁷

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—;

-   -   wherein R^(a) is hydrogen or C₁₋₆alkyl and b is 0-2;

Ring A is aryl or heteroaryl;

-   -   wherein Ring A is optionally substituted on carbon by one or        more substituents selected from R¹⁸;

R⁷ is hydrogen, C₁₋₆alkyl, carbocyclyl or heterocyclyl;

-   -   wherein R⁷ is optionally substituted on carbon by one or more        substituents selected from R¹⁹; and wherein if said heterocyclyl        contains an —NH— group, that nitrogen may be optionally        substituted by a group selected from R²⁰;

R⁸ is hydrogen or C₁₋₆-alkyl;

R⁹ is hydrogen or C₁₋₆alkyl;

R¹⁰ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkynyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino, N,N,N—(C₁₋₁₀alkyl)₃ammonio,C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl, N,N—(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N—(C₁₋₁₀alkyl)sulphamoyl,N,N—(C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀alkyl)sulphamoylamino,N,N—(C₁₋₁₀alkyl)₂sulphamoylamino, C₁₋₁₀alkoxycarbonylamino, carbocyclyl,carbocyclylC₁₋₁₀alkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²¹—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²²—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁰is optionally substituted on carbon by one or more substituents selectedfrom R²³; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁴; orR¹⁰ is a group of formula (VB):

wherein:

R¹¹ is hydrogen or C₁₋₆-alkyl;

R¹² and R¹³ are independently selected from hydrogen, halo, carbamoyl,sulphamoyl, C₁₋₁₀alkyl, C₂₋₁₀alkynyl, C₂₋₁₀alkynyl, C₁₋₁₀alkanoyl,N—(C₁₋₁₀alkyl)carbamoyl, N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a),wherein a is 0 to 2, N—(C₁₋₁₀alkyl)sulphamoyl,N,N—(C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀alkyl)sulphamoylamino,N,N—(C₁₋₁₀alkyl)₂sulphamoylamino, carbocyclyl or heterocyclyl; whereinR¹² and R¹ may be independently optionally substituted on carbon by oneor more substituents selected from R²⁵; and wherein if said heterocyclylcontains an —NH— group, that nitrogen may be optionally substituted by agroup selected from R²⁶;

R¹⁴ is selected from hydrogen, halo, carbamoyl, sulphamoyl,hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkanoyl, N—(C₁₋₁₀alkyl)carbamoyl, N,N—(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N—(C₁₋₁₀alkyl)sulphamoyl,N,N—(C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀alkyl)sulphamoylamino,N,N—(C₁₋₁₀alkyl)₂sulphamoylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²⁷—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²⁸—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁴may be optionally substituted on carbon by one or more substituentsselected from R²⁹; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R³; or R¹⁴ is a group of formula (VC):

R¹⁵ is hydrogen or C₁₋₆alkyl; and R¹⁶ is hydrogen or C₁₋₆alkyl; whereinR¹⁶ may be optionally substituted on carbon by one or more groupsselected from R³¹;

or R¹⁵ and R¹⁶ together with the nitrogen to which they are attachedform a heterocyclyl; wherein said heterocyclyl may be optionallysubstituted on carbon by one or more R³⁷; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R³⁸;

m is 1-3; wherein the values of R⁷ may be the same or different;

R¹⁷, R¹⁸, R¹⁹, R²³, R²⁵, R²⁹, R³¹ and R³⁷ are independently selectedfrom halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto,sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino, N,N,N—(C₁₋₁₀alkyl)₃ammonio,C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl, N,N—(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N—(C₁₋₁₀alkyl)sulphamoyl,N,N—(C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀alkyl)sulphamoylamino,N,N—(C₁₋₁₀alkyl)₂sulphamoylamino, C₁₋₁₀alkoxycarbonylamino, carbocyclyl,carbocyclylC₁₋₁₀alkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R³²—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R³³—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁷,R¹⁸, R¹⁹, R²³, R²⁵, R²⁹, R³¹ and R³⁷ may be independently optionallysubstituted on carbon by one or more R³⁴; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R³⁵;

R²¹, R²², R²⁷, R²⁸, R³² or R³³ are independently selected from —O—,—NR³⁶—, —S(O)_(x)—, —NR³⁶C(O)NR³⁶—, —NR³⁶C(S)NR³⁶—, —OC(O)N═C—,—NR³⁶C(O)— or —C(O)NR³⁶—; wherein R³⁶ is selected from hydrogen orC₁₋₆alkyl, and x is 0-2;

p, q, r and s are independently selected from 0-2;

R³⁴ is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino,nitro, carbamoyl, mercapto, sulphamoyl, trifluoromethyl,trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl,formyl, acetyl, formamido, acetylamino, acetoxy, methylamino,dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio,methylsulphinyl, mesyl, N-methylsulphamoyl, N,N-dimethylsulphamoyl,N-methylsulphamoylamino and N,N-dimethylsulphamoylamino;

R²⁰, R²⁴, R²⁶, R³⁰, R³⁵ and R³⁸ are independently selected fromC₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl,carbamoyl, N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl; and

wherein a “heteroaryl” is a totally unsaturated, mono or bicyclic ringcontaining 3-12 atoms of which at least one atom is chosen fromnitrogen, sulphur and oxygen, which heteroaryl may, unless otherwisespecified, be carbon or nitrogen linked;

wherein a “heterocyclyl” is a saturated, partially saturated orunsaturated, mono or bicyclic ring containing 3-12 atoms of which atleast one atom is chosen from nitrogen, sulphur and oxygen, whichheterocyclyl may, unless otherwise specified, be carbon or nitrogenlinked, wherein a —CH₂— group can optionally be replaced by a —C(O)—group, and a ring sulphur atom may be optionally oxidised to form anS-oxide; and

wherein a “carbocyclyl” is a saturated, partially saturated orunsaturated, mono or bicyclic carbon ring that contains 3-12 atoms;wherein a —CH₂— group can optionally be replaced by a —C(O) group; or apharmaceutically acceptable salt or in vivo hydrolysable ester or amideformed on an available carboxy or hydroxy group thereof.

In some embodiments, compound of Formula V is1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—(S)-1-[N—((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—{(R)-α-carboxy4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine,or a salt thereof.

In some embodiments, compound of Formula V is

In some embodiments, an ASBTI suitable for the methods described hereinis a compound of Formula VI:

wherein:

R^(v) and R^(w) are independently selected from hydrogen or C₁₋₆alkyl;

one of R¹ and R² is selected from hydrogen or C₁₋₆alkyl and the other isselected from C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen or C₁₋₆alkyl,or one of R^(x) and R^(y) is hydrogen or C₁₋₆alkyl and the other ishydroxy or C₁₋₆alkoxy;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl;

n is 0-5;

one of R⁴ and R⁵ is a group of formula (VIA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R⁷;

X is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₁₋₆alkyl and b is 0-2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedon carbon by one or more substituents selected from R¹⁸;

R⁷ is hydrogen, C₁₋₆alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted on carbon by one or more substituents selectedfrom R¹⁹; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁰;

R⁸ is hydrogen or C₁₋₆alkyl;

R⁹ is hydrogen or C₁₋₆alkyl;

R¹⁰ is hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino, N,N,N—(C₁₋₁₀alkyl)₃ammonio,C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl, N,N—(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N—(C₁₋₁₀alkyl)sulphamoyl,N,N—(C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀alkyl)sulphamoylamino,N,N—(C₁₋₁₀alkyl)₂sulphamoylamino, C₁₋₁₀alkoxycarbonylamino, carbocyclyl,carbocyclylC₁₋₁₀alkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²²—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁰is optionally substituted on carbon by one or more substituents selectedfrom R²³; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁴; orR¹⁰ is a group of formula (VIB):

wherein:

R¹¹ is hydrogen or C₁₋₆alkyl;

R¹² and R¹³ are independently selected from hydrogen, halo, nitro,cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl, N,N—(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N—(C₁₋₁₀alkyl)sulphamoyl,N,N—(C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀alkyl)sulphamoylamino,N,N—(C₁₋₁₀alkyl)₂sulphamoylamino, carbocyclyl or heterocyclyl; whereinR¹² and R¹³ may be independently optionally substituted on carbon by oneor more substituents selected from R²⁵; and wherein if said heterocyclylcontains an —NH— group, that nitrogen may be optionally substituted by agroup selected from R²⁶;

R¹⁴ is selected from hydrogen, halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N—(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²⁷—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²⁸—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁴may be optionally substituted on carbon by one or more substituentsselected from R²⁹; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R³⁰; or R¹⁴ is a group of formula (VIC):

R¹⁵ is hydrogen or C₁₋₆alkyl;

R¹⁶ is hydrogen or C₁₋₆alkyl; wherein R¹⁶ may be optionally substitutedon carbon by one or more groups selected from R³¹;

n is 1-3; wherein the values of R⁷ may be the same or different;

R¹⁷, R¹⁸, R¹⁹, R²³, R²⁵, R²⁹ or R³¹ are independently selected fromhalo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl,hydroxyaminocarbonyl, amidino, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy, (C₁₋₁₀alkyl)₃silyl,N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino, N,N,N—(C₁₋₁₀alkyl)₃ammonio,C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl, N,N—(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N—(C₁₋₁₀alkyl)sulphamoyl,N,N—(C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀alkyl)sulphamoylamino,N,N—(C₁₋₁₀alkyl)₂sulphamoylamino, C₁₋₁₀alkoxycarbonylamino, carbocyclyl,carbocyclylC₁₋₁₀alkyl, heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R³²—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R³³—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁷,R¹⁸, R¹⁹, R²³, R²⁵, R²⁹ or R³¹ may be independently optionallysubstituted on carbon by one or more R³⁴; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R³⁵;

R²¹, R²², R²⁷, R²⁸, R³² or R³³ are independently selected from —O—,—NR³⁶—, —S(O)_(x)—, —NR³⁶C(O)NR³⁶—, —NR³⁶C(S)NR³⁶—, —OC(O)N═C—,—NR³⁶C(O)— or —C(O)NR³⁶—; wherein R³⁶ is selected from hydrogen orC₁₋₆alkyl, and x is 0-2;

p, q, r and s are independently selected from 0-2;

R³⁴ is selected from halo, hydroxy, cyano, carbamoyl, ureido, amino,nitro, carbamoyl, mercapto, sulphamoyl, trifluoromethyl,trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl,formyl, acetyl, formamido, acetylamino, acetoxy, methylamino,dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio,methylsulphinyl, mesyl, N-methylsulphamoyl, N,N-dimethylsulphamoyl,N-methylsulphamoylamino and N,N-dimethylsulphamoylamino;

R²⁰, R²⁴, R²⁶, R³⁰ or R³⁵ are independently selected from C₁₋₆alkyl,C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl, carbamoyl,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)carbamoyl, benzyl,benzyloxycarbonyl, benzoyl and phenylsulphonyl;

or a pharmaceutically acceptable salt, solvate or solvate of such asalt, or an in vivo hydrolysable ester formed on an available carboxy orhydroxy thereof, or an in vivo hydrolysable amide formed on an availablecarboxy thereof.

In some embodiments, a compound of Formula VI has the structure ofFormula VID:

wherein:

R¹ and R² are independently selected from C₁₋₆alkyl; one of R⁴ and R⁵ isa group of formula (VIE):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino,N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,Cl₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁴;

R⁷ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(a))(OR^(b)),P(O)(OH)(OR_(a)), —P(O)(OH)(R^(a)) or P(O)(OR^(a))(R^(b)), wherein R^(a)and R^(b) are independently selected from C₁₋₆alkyl; or R⁷ is a group offormula (VIF):

R⁸ and R⁹ are independently hydrogen, C₁₋₄alkyl or a saturated cyclicgroup, or R⁸ and R⁹ together form C₂₋₆alkylene; wherein R⁸ and R⁹ or R⁸and R⁹ together may be independently optionally substituted on carbon byone or more substituents selected from R¹⁵; and wherein if saidsaturated cyclic group contains an —NH— moiety, that nitrogen may beoptionally substituted by one or more R²⁰;

R¹⁰ is hydrogen or C₁₋₄alkyl; wherein R¹⁰ is optionally substituted oncarbon by one or more substituents selected from R²⁴;

R¹¹ is hydrogen, C¹⁻⁴alkyl, carbocyclyl or heterocyclyl; wherein R¹¹ isoptionally substituted on carbon by one or more substituents selectedfrom R¹⁶; and wherein if said heterocyclyl contains an —NH— moiety, thatnitrogen may be optionally substituted by one or more R²¹;

R¹² is hydrogen or C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹²optionally substituted on carbon by one or more substituents selectedfrom R¹⁷; and wherein if said heterocyclyl contains an —NH— moiety, thatnitrogen may be optionally substituted by one or more R²;

R¹³ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —P(O)(OH)(R^(c)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆alkyl;

m is 1-3; wherein the values of R³ and R⁹ may be the same or different;

n is 1-3; wherein the values of R¹¹ may be the same or different;

p is 1-3; wherein the values of R¹² may be the same or different;

R¹⁴ and R¹⁶ are independently selected from halo, nitro, cyano, hydroxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O) whereina is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁴ and R¹⁶ may be independentlyoptionally substituted on carbon by one or more R¹⁸;

R¹⁵ and R¹⁷ are independently selected from halo, nitro, cyano, hydroxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino,amidino, phosphono, —P(O)(OR^(e))(OR^(f)), —P(O)(OH)(OR^(e)),—P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)), wherein R^(e) and R^(f) areindependently selected from C₁₋₆ alkyl; wherein R¹⁵ and R¹⁷ may beindependently optionally substituted on carbon by one or more R¹⁹; andwherein if said heterocyclyl contains an —NH— moiety, that nitrogen maybe optionally substituted by one or more R²³;

R¹⁸, R¹⁹ and R²⁵ are independently selected from halo, hydroxy, cyano,carbamoyl, ureido amino nitro, carboxy, carbamoyl, mercapto, sulphamoyl,trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy,vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido,acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl,N,N-dimethylcarbamoyl, methylthio, methylsulphinyl, mesyl,N-methylsulphamoyl and N,N-dimethylsulphamoyl;

R²⁰, R²¹, R²², R²³ and R²⁶ are independently C₁₋₄alkyl, C₁₋₄alkanoyl,C₁₋₄alkylsulphonyl, sulphamoyl, N—(C₁₋₄alkyl)sulphamoyl,N,N—(C₁₋₄alkyl)₂sulphamoyl, C₁₋₄alkoxycarbonyl, carbamoyl,N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, benzyl, phenethyl,benzoyl, phenylsulphonyl and phenyl;

R²⁴ is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino,N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl; wherein R²⁴ maybe independently optionally substituted on carbon by one or more R²⁵;and wherein if said heterocyclyl contains an —NH— moiety, that nitrogenmay be optionally substituted by one or more R²⁶;

wherein any saturated cyclic group is a totally or partially saturated,mono or bicyclic ring containing 3-12 atoms of which 0-4 atoms arechosen from nitrogen, sulphur or oxygen, which may be carbon or nitrogenlinked;

wherein any heterocyclyl is a saturated, partially saturated orunsaturated, mono or bicyclic ring containing 3-12 atoms of which atleast one atom is chosen from nitrogen, sulphur or oxygen, which may becarbon or nitrogen linked, wherein a —CH₂— group can optionally bereplaced by a —C(O)— or a ring sulphur atom may be optionally oxidisedto form the S-oxides; and

wherein any carbocyclyl is a saturated, partially saturated orunsaturated, mono or bicyclic carbon ring that contains 3-12 atoms,wherein a —CH₂— group can optionally be replaced by a —C(O—;

or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of Formula IV is1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—((R)-α-[N′—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl)carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N′—((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;or a salt thereof.

In some embodiments, any compound described herein is covalentlyconjugated to a bile acid using any suitable method. In someembodiments, compounds described herein are covalently bonded to acyclodextrin or a biodegradable polymer (e.g., a polysaccharide).

In certain embodiments compounds described herein are not systemicallyabsorbed. Moreover, provided herein are compounds that inhibit bile saltrecycling in the gastrointestinal tract of an individual. In someembodiments, compounds described herein, may not be transported from thegut lumen and/or do not interact with ASBT. In some embodiments,compounds described herein, do not affect, or minimally affect, fatdigestion and/or absorption. In certain embodiments, the administrationof a therapeutically effective amount of any compound described hereindoes not result in gastrointestinal disturbance or lactic acidosis in anindividual. In certain embodiments, compounds described herein areadministered orally. In some embodiments, an ASBTI is released in thedistal ileum. An ASBTI compatible with the methods described herein maybe a direct inhibitor, an allosteric inhibitor, or a partial inhibitorof the Apical Sodium-dependent Bile acid Transporter.

In certain embodiments, compounds that inhibit ASBT or any recuperativebile acid transporters are compounds that are described in EP1810689,U.S. Pat. Nos. 6,458,851, 7,413,536, 7,514,421, US Appl. PublicationNos. 2002/0147184, 2003/0119809, 2003/0149010, 2004/0014806,2004/0092500, 2004/0180861, 2004/0180860, 2005/0031651, 2006/0069080,2006/0199797, 2006/0241121, 2007/0065428, 2007/0066644, 2007/0161578,2007/0197628, 2007/0203183, 2007/0254952, 2008/0070888, 2008/0070892,2008/0070889, 2008/0070984, 2008/0089858, 2008/0096921, 2008/0161400,2008/0167356, 2008/0194598, 2008/0255202, 2008/0261990, WO 2002/50027,WO2005/046797, WO2006/017257, WO2006/105913, WO2006/105912,WO2006/116499, WO2006/117076, WO2006/121861, WO2006/122186,WO2006/124713, WO2007/050628, WO2007/101531, WO2007/134862,WO2007/140934, WO2007/140894, WO2008/028590, W2008/033431,WO2008/033464, WO2008/031501, WO2008/031500, WO2008/033465,WO2008/034534, WO2008/039829, WO2008/064788, WO2008/064789,WO2008/088836, WO2008/104306, WO2008/124505, and WO2008/130616; thecompounds described therein that inhibit recuperative bile acidtransport are hereby incorporated herein by reference.

In certain embodiments, compounds that inhibit ASBT or any recuperativebile acid transporters are compounds described in WO93/16055,WO94/18183, WO94/18184, WO96/05188, WO96/08484, WO96/16051, WO97/33882,WO98/38182, WO99/35135, WO98/40375, WO99/64409, WO99/64410, WO00/01687,WO00/47568, WO00/61568, DE 19825804, WO0/38725, WO0/38726, WO0/38727(including those compounds with a 2,3,4,5-tetrahydro-1-benzothiepine1,1-dioxide structure), WO00/38728, WO01/66533, WO02/50051, EP0864582(e.g.(3R,5R)-3-butyl-3-ethyl-1,1-dioxido-5-Phenyl-2,3,4,5-tetrahydro-1,4-benzo-thiazepin-8-yl(β-D-glucopyranosiduronic acid, WO94/24087, WO98/07749, WO98/56757,WO99/32478, WO99/35135, WO0/20392, WO00/20393, WO00/20410, WO0/20437,WO01/34570, WO00/35889, WO01/68637, WO01/68096, WO02/08211, WO03/020710,WO03/022825, WO03/022830, WO03/0222861, JP10072371, U.S. Pat. Nos.5,910,494; 5,723,458; 5,817,652; 5,663,165; 5,998,400; 6,465,451,5,994,391; 6,107,494; 6,387,924; 6,784,201; 6,875,877; 6,740,663;6,852,753; 5,070,103, 6,114,322, 6,020,330, 7,179,792, EP251315,EP417725, EP489-423, EP549967, EP573848, EP624593, EP624594, EP624595,EP869121, EP1070703, WO04/005247, compounds disclosed as having IBATactivity in Drugs of the Future, 24, 425-430 (1999), Journal ofMedicinal Chemistry, 48, 5837-5852, (2005) and Current MedicinalChemistry, 13, 997-1016, (2006); the compounds described therein thatinhibit recuperative bile acid transport are hereby incorporated hereinby reference.

In some embodiments, compounds that inhibit ASBT or any recuperativebile acid transporter are benzothiepines, benzothiazepines (including1,2-benzothiazepines; 1,4-benzothiazepines; 1,5-benzothiazepines; and/or1,2,5-benzothiadiazepines). In some embodiments, compounds that inhibitASBT or any recuperative bile acid transporter include and are notlimited to S-8921 (disclosed in EP597107, WO 93/08155), 264W94 (GSK)disclosed in WO 96/05188; SC-435(1-[4-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]4-aza-1-azoniabicyclo[2.2.2]octanemethanesulfonate salt), SC-635 (Searle); 2164U90(3-butyl-3-ethyl-2,3,4,5-tetrahydro-5-phenyl-1,4-benzothiazepine1,1-dioxide); BARI-1741 (Aventis SA), AZD 7508 (Astra Zeneca); barixibat(11-(D-gluconamido)-N-{2-[(1S,2R,3S)-3-hydroxy-3-phenyl-2-(2-pyridyl)-1-(2-pyridylamino)propyl]phenyl}undecanamide)or the like, or combinations thereof. In some embodiments, an ASBTI is:

In certain embodiments, compounds described herein have one or morechiral centers. As such, all stereoisomers are envisioned herein. Invarious embodiments, compounds described herein are present in opticallyactive or racemic forms. It is to be understood that the compounds ofthe present invention encompasses racemic, optically-active,regioisomeric and stereoisomeric forms, or combinations thereof thatpossess the therapeutically useful properties described herein.Preparation of optically active forms is achieve in any suitable manner,including by way of non-limiting example, by resolution of the racemicform by recrystallization techniques, by synthesis from optically-activestarting materials, by chiral synthesis, or by chromatographicseparation using a chiral stationary phase. In some embodiments,mixtures of one or more isomer is utilized as the therapeutic compounddescribed herein. In certain embodiments, compounds described hereincontains one or more chiral centers. These compounds are prepared by anymeans, including enantioselective synthesis and/or separation of amixture of enantiomers and/or diastereomers. Resolution of compounds andisomers thereof is achieved by any means including, by way ofnon-limiting example, chemical processes, enzymatic processes,fractional crystallization, distillation, chromatography, and the like.

The compounds described herein, and other related compounds havingdifferent substituents are synthesized using techniques and materialsdescribed herein and as described, for example, in Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), Larock's Comprehensive OrganicTransformations (VCH Publishers Inc., 1989), March, ADVANCED ORGANICCHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANICCHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000, 2001), and Green andWuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd) Ed., (Wiley 1999)(all of which are incorporated by reference for such disclosure).General methods for the preparation of compound as described herein aremodified by the use of appropriate reagents and conditions, for theintroduction of the various moieties found in the formulae as providedherein. As a guide the following synthetic methods are utilized.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

The compounds described herein are modified using various electrophilesand/or nucleophiles to form new functional groups or substituents. TableA entitled “Examples of Covalent Linkages and Precursors Thereof” listsselected non-limiting examples of covalent linkages and precursorfunctional groups which yield the covalent linkages. Table A is used asguidance toward the variety of electrophiles and nucleophilescombinations available that provide covalent linakges. Precursorfunctional groups are shown as electrophilic groups and nucleophilicgroups.

TABLE A Examples of Covalent Linkages and Precursors Thereof CovalentLinkage Product Electrophile Nucleophile Carboxamides Activated estersamines/anilines Carboxamides acyl azides amines/anilines Carboxamidesacyl halides amines/anilines Esters acyl halides alcohols/phenols Estersacyl nitriles alcohols/phenols Carboxamides acyl nitrilesamines/anilines Imines Aldehydes amines/anilines Hydrazones aldehydes orketones Hydrazines Oximes aldehydes or ketones Hydroxylamines Alkylamines alkyl halides amines/anilines Esters alkyl halides carboxylicacids Thioethers alkyl halides Thiols Ethers alkyl halidesalcohols/phenols Thioethers alkyl sulfonates Thiols Esters alkylsulfonates carboxylic acids Ethers alkyl sulfonates alcohols/phenolsEsters Anhydrides alcohols/phenols Carboxamides Anhydridesamines/anilines Thiophenols aryl halides Thiols Aryl amines aryl halidesAmines Thioethers Azindines Thiols Boronate esters Boronates GlycolsCarboxamides carboxylic acids amines/anilines Esters carboxylic acidsAlcohols hydrazines Hydrazides carboxylic acids N-acylureas orAnhydrides carbodiimides carboxylic acids Esters diazoalkanes carboxylicacids Thioethers Epoxides Thiols Thioethers haloacetamides ThiolsAmmotriazines halotriazines amines/anilines Triazinyl ethershalotriazines alcohols/phenols Amidines imido esters amines/anilinesUreas Isocyanates amines/anilines Urethanes Isocyanates alcohols/phenolsThioureas isothiocyanates amines/anilines Thioethers Maleimides ThiolsPhosphite esters phosphoramidites Alcohols Silyl ethers silyl halidesAlcohols Alkyl amines sulfonate esters amines/anilines Thioetherssulfonate esters Thiols Esters sulfonate esters carboxylic acids Etherssulfonate esters Alcohols Sulfonamides sulfonyl halides amines/anilinesSulfonate esters sulfonyl halides phenols/alcohols

Use of Protecting Groups

In the reactions described, it is necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, in order to avoidtheir unwanted participation in reactions. Protecting groups are used toblock some or all of the reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. In some embodiments it is contemplated that each protectivegroup be removable by a different means. Protective groups that arecleaved under totally disparate reaction conditions fulfill therequirement of differential removal.

In some embodiments, protective groups are removed by acid, base,reducing conditions (such as, for example, hydrogenolysis), and/oroxidative conditions. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and are used to protect carboxy andhydroxy reactive moieties in the presence of amino groups protected withCbz groups, which are removable by hydrogenolysis, and Fmoc groups,which are base labile. Carboxylic acid and hydroxy reactive moieties areblocked with base labile groups such as, but not limited to, methyl,ethyl, and acetyl in the presence of amines blocked with acid labilegroups such as t-butyl carbamate or with carbamates that are both acidand base stable but hydrolytically removable.

In some embodiments carboxylic acid and hydroxy reactive moieties areblocked with hydrolytically removable protective groups such as thebenzyl group, while amine groups capable of hydrogen bonding with acidsare blocked with base labile groups such as Fmoc. Carboxylic acidreactive moieties are protected by conversion to simple ester compoundsas exemplified herein, which include conversion to alkyl esters, or areblocked with oxidatively-removable protective groups such as2,4-dimethoxybenzyl, while co-existing amino groups are blocked withfluoride labile silyl carbamates.

Allyl blocking groups are useful in the presence of acid- andbase-protecting groups since the former are stable and are subsequentlyremoved by metal or pi-acid catalysts. For example, an allyl-blockedcarboxylic acid is deprotected with a Pd°-catalyzed reaction in thepresence of acid labile t-butyl carbamate or base-labile acetate amineprotecting groups. Yet another form of protecting group is a resin towhich a compound or intermediate is attached. As long as the residue isattached to the resin, that functional group is blocked and does notreact. Once released from the resin, the functional group is availableto react.

Typically blocking/protecting groups are selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference for such disclosure.

In some embodiments, ASBTIs described herein are synthesized asdescribed in, for example, WO 96/05188, U.S. Pat. Nos. 5,994,391;7,238,684; 6,906,058; 6,020,330; and 6,114,322. In some embodiments,ASBTIs described herein are synthesized starting from compounds that areavailable from commercial sources or that are prepared using proceduresoutlined herein. In some embodiments, compounds described herein areprepared according to the process set forth in Scheme 1:

In certain embodiments, the synthesis begins with a reaction of1,4-diazabicyclo[2.2.2]octane with 4-iodo-1-chloro butane to provide acompound of structure 1-I. Such compounds are prepared in any suitablemanner, e.g., as set forth in Tremont, S. J. et. al., J. Med. Chem.2005, 48, 5837-5852. The compound of structure 1-I is then subjected toa reaction with phenethylamine to provide a compound of structure 1-II.The compound of structure 1-II is then allowed to react withdicyanodiamide to provide a compound of Formula I.

In some embodiments, a first compound of Formula III is subjected to afurther reaction to provide a second compound of Formula III as shown inScheme 2 below.

A first compound of Formula III, 1-IA, is alkylated with iodomethane toprovide a second compound of Formula III, 1-IB. Alkylation of 1-IB witha compound of structure 2-II provides a further compound of Formula III,IC. In an alternative embodiment, a first compound of Formula III, 1-IA,is alkylated with a compound of structure 2-I to provide a secondcompound of Formula III, 1-IC

In some embodiments, compounds described herein are prepared accordingto the process set forth in Scheme 3:

General Definitions

The term “bile acid,” as used herein, includes steroid acids (and/or thecarboxylate anion thereof), and salts thereof, found in the bile of ananimal (e.g., a human), including, by way of non-limiting example,cholic acid, cholate, deoxycholic acid, deoxycholate, hyodeoxycholicacid, hyodeoxycholate, glycocholic acid, glycocholate, taurocholic acid,taurocholate, chenodeoxycholic acid, ursodeoxycholic acid, ursodiol, atauroursodeoxycholic acid, a glycoursodeoxycholic acid, a 7-B-methylcholic acid, a methyl lithocholic acid, chenodeoxycholate, lithocholicacid, lithocolate, and the like. Taurocholic acid and/or taurocholateare referred to herein as TCA Any reference to a bile acid used hereinincludes reference to a bile acid, one and only one bile acid, one ormore bile acids, or to at least one bile acid. Therefore, the terms“bile acid,” “bile salt,” “bile acid/salt,” “bile acids,” “bile salts,”and “bile acids/salts” are, unless otherwise indicated, utilizedinterchangeably herein. Any reference to a bile acid used hereinincludes reference to a bile acid or a salt thereof. Furthermore,pharmaceutically acceptable bile acid esters are optionally utilized asthe “bile acids” described herein, e.g., bile acids/salts conjugated toan amino acid (e.g., glycine or taurine). Other bile acid estersinclude, e.g., substituted or unsubstituted alkyl ester, substituted orunsubstituted heteroalkyl esters, substituted or unsubstituted arylesters, substituted or unsubstituted heteroaryl esters, or the like. Forexample, the term “bile acid” includes cholic acid conjugated witheither glycine or taurine: glycocholate and taurocholate, respectively(and salts thereof). Any reference to a bile acid used herein includesreference to an identical compound naturally or synthetically prepared.Furthermore, it is to be understood that any singular reference to acomponent (bile acid or otherwise) used herein includes reference to oneand only one, one or more, or at least one of such components.Similarly, any plural reference to a component used herein includesreference to one and only one, one or more, or at least one of suchcomponents, unless otherwise noted. Moreover, as used herein, bileacid/salt mimics or mimetics described herein are compounds that mimicthe agonist signaling properties of the bile acid/salt, especially atTGR5 (GPBAR1, BG37, Axor109) receptors. Examples include those describedin WO 2010/014836, which is incorporated herein for such disclosure. Insome embodiments, bile acid mimetics include triterpenoid, such asoleanoic acid, ursolic acid, or the like.

The term “subject”, “patient” or “individual” are used interchangeablyherein and refer to mammals and non-mammals, e.g., suffering from adisorder described herein. Examples of mammals include, but are notlimited to, any member of the mammalian class: humans, non-humanprimates such as chimpanzees, and other apes and monkey species; farmanimals such as cattle, horses, sheep, goats, swine; domestic animalssuch as rabbits, dogs, and cats; laboratory animals including rodents,such as rats, mice and guinea pigs, and the like. Examples ofnon-mammals include, but are not limited to, birds, fish and the like.In one embodiment of the methods and compositions provided herein, themammal is a human.

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions given belowwith regard to “pediatric” or “pediatric patients” includes Neonatal(children ages 0 to 4 weeks), Infant Children (ages 4 weeks to 2 years),Children (ages 2 to 5 years), Children (ages 6 to 11 years) andAdolescents (12 to 18 years).

The term “about,” as used herein, includes any value that is within 10%of the described value.

The term “between,” as used herein, is inclusive of the lower and uppernumber of the range.

The term “colon,” as used herein, includes the cecum, ascending colon,hepatic flexure, splenic flexure, descending colon, and sigmoid.

The term “composition,” as used herein includes the disclosure of both acomposition and a composition administered in a method as describedherein. Furthermore, in some embodiments, the composition of the presentinvention is or comprises a “formulation,” an oral dosage form or arectal dosage form as described herein.

The terms “treat,” “treating” or “treatment,” and other grammaticalequivalents as used herein, include alleviating, inhibiting or reducingsymptoms, reducing or inhibiting severity of, reducing incidence of,reducing or inhibiting recurrence of, delaying onset of, delayingrecurrence of, abating or ameliorating a disease or condition symptoms,ameliorating the underlying causes of symptoms, inhibiting the diseaseor condition, e.g., arresting the development of the disease orcondition, relieving the disease or condition, causing regression of thedisease or condition, relieving a condition caused by the disease orcondition, or stopping the symptoms of the disease or condition. Theterms further include achieving a therapeutic benefit. By therapeuticbenefit is meant eradication or amelioration of the underlying disorderbeing treated, and/or the eradication or amelioration of one or more ofthe physiological symptoms associated with the underlying disorder suchthat an improvement is observed in the patient.

The terms “prevent,” “preventing” or “prevention,” and other grammaticalequivalents as used herein, include preventing additional symptoms,preventing the underlying causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or conditionand are intended to include prophylaxis. The terms further includeachieving a prophylactic benefit. For prophylactic benefit, thecompositions are optionally administered to a patient at risk ofdeveloping a particular disease, to a patient reporting one or more ofthe physiological symptoms of a disease, or to a patient at risk ofreoccurrence of the disease.

Where combination treatments or prevention methods are contemplated, itis not intended that the agents described herein be limited by theparticular nature of the combination. For example, the agents describedherein are optionally administered in combination as simple mixtures aswell as chemical hybrids. An example of the latter is where the agent iscovalently linked to a targeting carrier or to an active pharmaceutical.Covalent binding can be accomplished in many ways, such as, though notlimited to, the use of a commercially available cross-linking agent.Furthermore, combination treatments are optionally administeredseparately or concomitantly.

As used herein, the terms “pharmaceutical combination”, “administeringan additional therapy”, “administering an additional therapeutic agent”and the like refer to a pharmaceutical therapy resulting from the mixingor combining of more than one active ingredient and includes both fixedand non-fixed combinations of the active ingredients. The term “fixedcombination” means that at least one of the agents described herein, andat least one co-agent, are both administered to a patient simultaneouslyin the form of a single entity or dosage. The term “non-fixedcombination” means that at least one of the agents described herein, andat least one co-agent, are administered to a patient as separateentities either simultaneously, concurrently or sequentially withvariable intervening time limits, wherein such administration provideseffective levels of the two or more agents in the body of the patient.In some instances, the co-agent is administered once or for a period oftime, after which the agent is administered once or over a period oftime. In other instances, the co-agent is administered for a period oftime, after which, a therapy involving the administration of both theco-agent and the agent are administered. In still other embodiments, theagent is administered once or over a period of time, after which, theco-agent is administered once or over a period of time. These also applyto cocktail therapies, e.g. the administration of three or more activeingredients.

As used herein, the terms “co-administration”, “administered incombination with” and their grammatical equivalents are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different times. In some embodiments the agentsdescribed herein will be co-administered with other agents. These termsencompass administration of two or more agents to an animal so that bothagents and/or their metabolites are present in the animal at the sametime. They include simultaneous administration in separate compositions,administration at different times in separate compositions, and/oradministration in a composition in which both agents are present. Thus,in some embodiments, the agents described herein and the other agent(s)are administered in a single composition. In some embodiments, theagents described herein and the other agent(s) are admixed in thecomposition.

The terms “effective amount” or “therapeutically effective amount” asused herein, refer to a sufficient amount of at least one agent beingadministered which achieve a desired result, e.g., to relieve to someextent one or more symptoms of a disease or condition being treated. Incertain instances, the result is a reduction and/or alleviation of thesigns, symptoms, or causes of a disease, or any other desired alterationof a biological system. In certain instances, an “effective amount” fortherapeutic uses is the amount of the composition comprising an agent asset forth herein required to provide a clinically significant decreasein a disease. An appropriate “effective” amount in any individual caseis determined using any suitable technique, such as a dose escalationstudy.

The terms “administer,” “administering”, “administration,” and the like,as used herein, refer to the methods that may be used to enable deliveryof agents or compositions to the desired site of biological action.These methods include, but are not limited to oral routes, intraduodenalroutes, parenteral injection (including intravenous, subcutaneous,intraperitoneal, intramuscular, intravascular or infusion), topical andrectal administration. Administration techniques that are optionallyemployed with the agents and methods described herein are found insources e.g., Goodman and Gilman, The Pharmacological Basis ofTherapeutics, current ed.; Pergamon; and Remington's, PharmaceuticalSciences (current edition), Mack Publishing Co., Easton, Pa. In certainembodiments, the agents and compositions described herein areadministered orally.

The term “pharmaceutically acceptable” as used herein, refers to amaterial that does not abrogate the biological activity or properties ofthe agents described herein, and is relatively nontoxic (i.e., thetoxicity of the material significantly outweighs the benefit of thematerial). In some instances, a pharmaceutically acceptable material maybe administered to an individual without causing significant undesirablebiological effects or significantly interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

The term “carrier” as used herein, refers to relatively nontoxicchemical agents that, in certain instances, facilitate the incorporationof an agent into cells or tissues.

The term “non-systemic” or “minimally absorbed” as used herein refers tolow systemic bioavailability and/or absorption of an administeredcompound. In some instances a non-systemic compound is a compound thatis substantially not absorbed systemically. In some embodiments, ASBTIcompositions described herein deliver the ASBTI to the distal ileum,colon, and/or rectum and not systemically (e.g., a substantial portionof the ASBTI is not systemically absorbed. In some embodiments, thesystemic absorption of a non-systemic compound is <0.1%, <0.3%, <0.5%,<0.6%, <0.7%, <0.8%, <0.9%, <1%, <1.5%, <2%, <3%, or <5% of theadministered dose (wt. % or mol %). In some embodiments, the systemicabsorption of a non-systemic compound is <10% of the administered dose.In some embodiments, the systemic absorption of a non-systemic compoundis <15% of the administered dose. In some embodiments, the systemicabsorption of a non-systemic compound is <25% of the administered dose.In an alternative approach, a non-systemic ASBTI is a compound that haslower systemic bioavailability relative to the systemic bioavailabilityof a systemic ASBTI (e.g., compound 100A, 100C). In some embodiments,the bioavailability of a non-systemic ASBTI described herein is <30%,<40%, <50%, <60%, or <70% of the bioavailability of a systemic ASBTI(e.g., compound 100A, 100C).

In another alternative approach, the compositions described herein areformulated to deliver <10% of the administered dose of the ASBTIsystemically. In some embodiments, the compositions described herein areformulated to deliver <20% of the administered dose of the ASBTIsystemically. In some embodiments, the compositions described herein areformulated to deliver <30% of the administered dose of the ASBTIsystemically. In some embodiments, the compositions described herein areformulated to deliver <40% of the administered dose of the ASBTIsystemically. In some embodiments, the compositions described herein areformulated to deliver <50% of the administered dose of the ASBTIsystemically. In some embodiments, the compositions described herein areformulated to deliver <60% of the administered dose of the ASBTIsystemically. In some embodiments, the compositions described herein areformulated to deliver <70% of the administered dose of the ASBTIsystemically. In some embodiments, systemic absorption is determined inany suitable manner, including the total circulating amount, the amountcleared after administration, or the like.

The term “ASBT inhibitor” refers to a compound that inhibits apicalsodium-dependent bile transport or any recuperative bile salt transport.The term Apical Sodium-dependent Bile Transporter (ASBT) is usedinterchangeably with the term Ileal Bile Acid Transporter (IBAT).

The term “enhancing enteroendocrine peptide secretion” refers to asufficient increase in the level of the enteroendocrine peptide agent,for example, to treat any disease or disorder described herein. In someembodiments, enhanced enteroendocrine peptide secretion reverses oralleviates symptoms of cholestasis or a cholestatic liver disease.

In various embodiments, pharmaceutically acceptable salts describedherein include, by way of non-limiting example, a nitrate, chloride,bromide, phosphate, sulfate, acetate, hexafluorophosphate, citrate,gluconate, benzoate, propionate, butyrate, sulfosalicylate, maleate,laurate, malate, fumarate, succinate, tartrate, amsonate, pamoate,p-tolunenesulfonate, mesylate and the like. Furthermore,pharmaceutically acceptable salts include, by way of non-limitingexample, alkaline earth metal salts (e.g., calcium or magnesium), alkalimetal salts (e.g., sodium-dependent or potassium), ammonium salts andthe like.

The term “optionally substituted” or “substituted” means that thereferenced group substituted with one or more additional group(s). Incertain embodiments, the one or more additional group(s) areindividually and independently selected from amide, ester, alkyl,cycloalkyl, heteroalkyl, aryl, heteroaryl, heteroalicyclic, hydroxy,alkoxy, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide,ester, alkylsulfone, arylsulfone, cyano, halo, alkoyl, alkoyloxo,isocyanato, thiocyanato, isothiocyanato, nitro, haloalkyl, haloalkoxy,fluoroalkyl, amino, alkyl-amino, dialkyl-amino, amido.

An “alkyl” group refers to an aliphatic hydrocarbon group. Reference toan alkyl group includes “saturated alkyl” and/or “unsaturated alkyl”.The alkyl group, whether saturated or unsaturated, includes branched,straight chain, or cyclic groups. By way of example only, alkyl includesmethyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,t-butyl, pentyl, iso-pentyl, neo-pentyl, and hexyl. In some embodiments,alkyl groups include, but are in no way limited to, methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl,ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and the like. A “lower alkyl” is a C₁-C₆ alkyl. A“heteroalkyl” group substitutes any one of the carbons of the alkylgroup with a heteroatom having the appropriate number of hydrogen atomsattached (e.g., a CH₂ group to an NH group or an O group).

The term “alkylene” refers to a divalent alkyl radical. Any of the abovementioned monovalent alkyl groups may be an alkylene by abstraction of asecond hydrogen atom from the alkyl. In one aspect, an alkelene is aC₁-C₁₀alkylene. In another aspect, an alkylene is a C₁-C₆alkylene.Typical alkylene groups include, but are not limited to, —CH₂—,—CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—, —CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂—, and the like.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, whereinalkyl is as defined herein and x and y are selected from the group x=1,y=1 and x=2, y=O. When x=2, the alkyl groups, taken together with thenitrogen to which they are attached, optionally form a cyclic ringsystem.

An “amide” is a chemical moiety with formula —C(O)NHR or —NHC(O)R, whereR is selected from alkyl, cycloalkyl, aryl, heteroaryl (bonded through aring carbon) and heteroalicyclic (bonded through a ring carbon).

The term “ester” refers to a chemical moiety with formula —C(═O)OR,where R is selected from the group consisting of alkyl, cycloalkyl,aryl, heteroaryl and heteroalicyclic.

As used herein, the term “aryl” refers to an aromatic ring wherein eachof the atoms forming the ring is a carbon atom. Aryl rings describedherein include rings having five, six, seven, eight, nine, or more thannine carbon atoms. Aryl groups are optionally substituted. Examples ofaryl groups include, but are not limited to phenyl, and naphthalenyl.

The term “aromatic” refers to a planar ring having a delocalizedx-electron system containing 4n+2 π electrons, where n is an integer.Aromatic rings can be formed from five, six, seven, eight, nine, ten, ormore than ten atoms. Aromatics are optionally substituted. The term“aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) andheterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g.,pyridine). The term includes monocyclic or fused-ring polycyclic (i.e.,rings which share adjacent pairs of carbon atoms) groups.

The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromaticradical, wherein each of the atoms forming the ring (i.e. skeletalatoms) is a carbon atom. In various embodiments, cycloalkyls aresaturated, or partially unsaturated. In some embodiments, cycloalkylsare fused with an aromatic ring. Cycloalkyl groups include groups havingfrom 3 to 10 ring atoms. Illustrative examples of cycloalkyl groupsinclude, but are not limited to, the following moieties:

and the like. Monocyclic cycloalkyls include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl.

The term “heterocyclo” refers to heteroaromatic and heteroalicyclicgroups containing one to four ring heteroatoms each selected from O, Sand N. In certain instances, each heterocyclic group has from 4 to 10atoms in its ring system, and with the proviso that the ring of saidgroup does not contain two adjacent O or S atoms. Non-aromaticheterocyclic groups include groups having 3 atoms in their ring system,but aromatic heterocyclic groups must have at least 5 atoms in theirring system. The heterocyclic groups include benzo-fused ring systems.An example of a 3-membered heterocyclic group is aziridinyl (derivedfrom aziridine). An example of a 4-membered heterocyclic group isazetidinyl (derived from azetidine). An example of a 5-memberedheterocyclic group is thiazolyl. An example of a 6-membered heterocyclicgroup is pyridyl, and an example of a 10-membered heterocyclic group isquinolinyl. Examples of non-aromatic heterocyclic groups arepyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl,tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino,morpholino, thiomorpholino, thioxanyl, piperazinyl, aziridinyl,azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl,oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl,2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl,1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl,dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl,imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl,3H-indolyl and quinolizinyl. Examples of aromatic heterocyclic groupsare pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl,tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl,isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl,benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl,phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl,oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl,benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,naphthyridinyl, and furopyridinyl.

The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to anaryl group that includes one or more ring heteroatoms selected fromnitrogen, oxygen and sulfur. An N-containing “heteroaromatic” or“heteroaryl” moiety refers to an aromatic group in which at least one ofthe skeletal atoms of the ring is a nitrogen atom. In certainembodiments, heteroaryl groups are monocyclic or polycyclic.Illustrative examples of heteroaryl groups include the followingmoieties:

and the like.

A “heteroalicyclic” group or “heterocyclo” group refers to a cycloalkylgroup, wherein at least one skeletal ring atom is a heteroatom selectedfrom nitrogen, oxygen and sulfur. In various embodiments, the radicalsare with an aryl or heteroaryl. Illustrative examples of heterocyclogroups, also referred to as non-aromatic heterocycles, include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides.

The term “halo” or, alternatively, “halogen” means fluoro, chloro, bromoand iodo.

The terms “haloalkyl,” and “haloalkoxy” include alkyl and alkoxystructures that are substituted with one or more halogens. Inembodiments, where more than one halogen is included in the group, thehalogens are the same or they are different. The terms “fluoroalkyl” and“fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, inwhich the halo is fluorine.

The term “heteroalkyl” include optionally substituted alkyl, alkenyl andalkynyl radicals which have one or more skeletal chain atoms selectedfrom an atom other than carbon, e.g., oxygen, nitrogen, sulfur,phosphorus, silicon, or combinations thereof. In certain embodiments,the heteroatom(s) is placed at any interior position of the heteroalkylgroup. Examples include, but are not limited to, —CH₂—O—CH₃,—CH₂—CH₂—O—CH₃, —CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃,—CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂,—S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,and —CH═CH—N(CH₃)—CH₃. In some embodiments, up to two heteroatoms areconsecutive, such as, by way of example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃.

A “cyano” group refers to a —CN group.

An “isocyanato” group refers to a —NCO group.

A “thiocyanato” group refers to a —CNS group.

An “isothiocyanato” group refers to a —NCS group.

“Alkoyloxy” refers to a RC(═O)O— group.

“Alkoyl” refers to a RC(═O)— group.

The term “modulate,” as used herein refers to having some affect on(e.g., increasing, enhancing or maintaining a certain level).

The term “optionally substituted” or “substituted” means that thereferenced group may be substituted with one or more additional group(s)individually and independently selected from C₁-C₆alkyl,C₃-C₈cycloalkyl, aryl, heteroaryl, C₂-C₆heteroalicyclic, hydroxy,C₁-C₆alkoxy, aryloxy, arylalkoxy, aralkyloxy, arylalkyloxy,C₁-C₆alkylthio, arylthio, C₁-C₆alkylsulfoxide, arylsulfoxide,C₁-C₆alkylsulfone, arylsulfone, cyano, halo, C₂-C₈acyl, C₂-C₈acyloxy,nitro, C₁-C₆haloalkyl, C₁-C₆fluoroalkyl, and amino, includingC-C₆alkylamino, and the protected derivatives thereof. By way ofexample, an optional substituents may be L^(s)R^(s), wherein each L^(s)is independently selected from a bond, —O—, —C(═O)—, —S—, —S(═O)—,—S(═O)₂—, —NH—, —NHC(═O)—, —C(═O)NH—, S(═O)₂NH—, —NHS(═O)₂—, —OC(═O)NH—,—NHC(═O)O—, —(C₁-C₆alkyl)-, or —(C₂-C₆alkenyl)-; and each R^(s) isindependently selected from H, (C₁-C₄alkyl), (C₃-C₈cycloalkyl),heteroaryl, aryl, and C₁-C₆heteroalkyl. Optionally substitutednon-aromatic groups may be substituted with one or more oxo (═O). Theprotecting groups that may form the protective derivatives of the abovesubstituents are known to those of skill in the art and may be found inreferences such as Greene and Wuts, above. In some embodiments, alkylgroups described herein are optionally substituted with an O that isconnected to two adjacent carbon atoms (i.e., forming an epoxide).

The term “therapeutically effective amount” or an “effective amount” asused herein, refers to a sufficient amount of a therapeutically activeagent to provide a desired effect in a subject or individual. In someembodiments, a “therapeutically effective amount” or an “effectiveamount” of an ASBTI refers to a sufficient amount of an ASBTI to treatcholestasis or a cholestatic liver disease in a subject or individual.

L-Cells

Inventors have discovered that enteroendocrine L-cells play a role inrepair. The epithelial barrier is also a key component in host defence.A further pre-proglucagon splice product, GLP-2, is secreted byenteroendocrine L-cells in the distal small intestine and has been shownto improve intestinal wound healing in a TGF-B (anti-inflammatorycytokine TGF-B), mediated process, small bowel responding better thanlarge bowel. GLP-2 has also been shown to ameliorate the barrierdysfunction induced by experimental stress and food allergy. Again,L-cells are activated by luminal nutrients, and the barrier compromiseobserved in TPN may partly reflect its hyposecretion in the absence ofenteral stimuli. Moreover, GLP-2 is also responsible, at least in partfor growth and adaptation observed in short-bowel models. Therefore,abnormal enteroendocrine cells (EEC) function may predispose to GIinflammatory disorders, and the underlying nutrient-EEC-vagal pathwaysare targets in the injured gut as contemplated in the presentembodiments.

L-cells are scattered throughout the epithelial layer of the gut fromthe duodenum to the rectum, with the highest numbers occurring in theileum, colon, and rectum. They are characterized by an open-cellmorphology, with apical microvilli facing into the gut lumen andsecretory vesicles located adjacent to the basolateral membrane, and aretherefore in direct contact with nutrients in the intestinal lumen.Furthermore, L-cells are located in close proximity to both neurons andthe microvasculature of the intestine, thereby allowing the L-cell to beaffected by both neural and hormonal signals. As well as Glucagon-LikePeptide 1 (GLP-1) and Glucagon-Like Peptide 2 (GLP-2), L-cells alsosecrete peptide YY (PYY), and glutamate. The cells are just one memberof a much larger family of enteroendocrine cells that secrete a range ofhormones, including ghrelin, GIP, cholecystokinin, somatostatin, andsecretin, which are involved in the local coordination of gutphysiology, as well as in playing wider roles in the control of cytokinerelease and/or controlling the adaptive process, attenuating intestinalinjury, reducing bacterial translocation, inhibiting the release of freeradical oxygen, or any combination thereof. L-cells are unevenlydistributed in the gastrointestinal tract, within higher concentrationsin the distal portion of the gastrointestinal tract (e.g., in the distalileum, colon and rectum).

Bile Acid

Bile contains water, electrolytes and a numerous organic moleculesincluding bile acids, cholesterol, phospholipids and bilirubin. Bile issecreted from the liver and stored in the gall bladder, and upon gallbladder contraction, due to ingestion of a fatty meal, bile passesthrough the bile duct into the intestine. Bile acids/salts are criticalfor digestion and absorption of fats and fat-soluble vitamins in thesmall intestine. Adult humans produce 400 to 800 mL of bile daily. Thesecretion of bile can be considered to occur in two stages. Initially,hepatocytes secrete bile into canaliculi, from which it flows into bileducts and this hepatic bile contains large quantities of bile acids,cholesterol and other organic molecules. Then, as bile flows through thebile ducts, it is modified by addition of a watery, bicarbonate-richsecretion from ductal epithelial cells. Bile is concentrated, typicallyfive-fold, during storage in the gall bladder.

The flow of bile is lowest during fasting, and a majority of that isdiverted into the gallbladder for concentration. When chyme from aningested meal enters the small intestine, acid and partially digestedfats and proteins stimulate secretion of cholecystokinin and secretin,both of which are important for secretion and flow of bile.Cholecystokinin (cholecysto=gallbladder and kinin=movement) is a hormonewhich stimulates contractions of the gallbladder and common bile duct,resulting in delivery of bile into the gut. The most potent stimulus forrelease of cholecystokinin is the presence of fat in the duodenum.Secretin is a hormone secreted in response to acid in the duodenum, andit simulates biliary duct cells to secrete bicarbonate and water, whichexpands the volume of bile and increases its flow out into theintestine.

Bile acids/salts are derivatives of cholesterol. Cholesterol, ingestedas part of the diet or derived from hepatic synthesis, are convertedinto bile acids/salts in the hepatocyte. Examples of such bileacids/salts include cholic and chenodeoxycholic acids, which are thenconjugated to an amino acid (such as glycine or taurine) to yield theconjugated form that is actively secreted into cannaliculi. The mostabundant of the bile salts in humans are cholate and deoxycholate, andthey are normally conjugated with either glycine or taurine to giveglycocholate or taurocholate respectively.

Free cholesterol is virtually insoluble in aqueous solutions, however inbile it is made soluble by the presence of bile acids/salts and lipids.Hepatic synthesis of bile acids/salts accounts for the majority ofcholesterol breakdown in the body. In humans, roughly 500 mg ofcholesterol are converted to bile acids/salts and eliminated in bileevery day. Therefore, secretion into bile is a major route forelimination of cholesterol. Large amounts of bile acids/salts aresecreted into the intestine every day, but only relatively smallquantities are lost from the body. This is because approximately 95% ofthe bile acids/salts delivered to the duodenum are absorbed back intoblood within the ileum, by a process is known as “EnterohepaticRecirculation”.

Venous blood from the ileum goes straight into the portal vein, andhence through the sinusoids of the liver. Hepatocytes extract bileacids/salts very efficiently from sinusoidal blood, and little escapesthe healthy liver into systemic circulation. Bile acids/salts are thentransported across the hepatocytes to be resecreted into canaliculi. Thenet effect of this enterohepatic recirculation is that each bile saltmolecule is reused about 20 times, often two or three times during asingle digestive phase. Bile biosynthesis represents the major metabolicfate of cholesterol, accounting for more than half of the approximate800 mg/day of cholesterol that an average adult uses up in metabolicprocesses. In comparison, steroid hormone biosynthesis consumes onlyabout 50 mg of cholesterol per day. Much more that 400 mg of bile saltsis required and secreted into the intestine per day, and this isachieved by re-cycling the bile salts. Most of the bile salts secretedinto the upper region of the small intestine are absorbed along with thedietary lipids that they emulsified at the lower end of the smallintestine. They are separated from the dietary lipid and returned to theliver for re-use. Re-cycling thus enables 20-30 g of bile salts to besecreted into the small intestine each day.

Bile acids/salts are amphipathic, with the cholesterol-derived portioncontaining both hydrophobic (lipid soluble) and polar (hydrophilic)moieties while the amino acid conjugate is generally polar andhydrophilic. This amphipathic nature enables bile acids/salts to carryout two important functions: emulsification of lipid aggregates andsolubilization and transport of lipids in an aqueous environment. Bileacids/salts have detergent action on particles of dietary fat whichcauses fat globules to break down or to be emulsified. Emulsification isimportant since it greatly increases the surface area of fat availablefor digestion by lipases which cannot access the inside of lipiddroplets. Furthermore, bile acids/salts are lipid carriers and are ableto solubilize many lipids by forming micelles and are critical fortransport and absorption of the fat-soluble vitamins.

Pharmaceutical Compositions and Methods of Use

In some embodiments, compositions described herein are administered fordelivery of enteroendocrine peptide secretion enhancing agents to asubject or individual. In certain embodiments, any compositionsdescribed herein are formulated for ileal, rectal and/or colonicdelivery. In more specific embodiments, the composition is formulatedfor non-systemic or local delivery to the rectum and/or colon. It is tobe understood that as used herein, delivery to the colon includesdelivery to sigmoid colon, transverse colon, and/or ascending colon. Instill more specific embodiments, the composition is formulated fornon-systemic or local delivery to the rectum and/or colon isadministered rectally. In other specific embodiments, the composition isformulated for non-systemic or local delivery to the rectum and/or colonis administered orally.

In some embodiments, provided herein is a composition comprising anenteroendocrine peptide secretion enhancing agent and, optionally, apharmaceutically acceptable carrier for alleviating symptoms ofpediatric cholestasis or a pediatric cholestatic liver disease in anindividual.

In certain embodiments, the composition comprises an enteroendocrinepeptide secretion enhancing agent and an absorption inhibitor. Inspecific embodiments, the absorption inhibitor is an inhibitor thatinhibits the absorption of the (or at least one of the) specificenteroendocrine peptide secretion enhancing agent with which it iscombined. In some embodiments, the composition comprises anenteroendocrine peptide secretion enhancing agent, an absorptioninhibitor and a carrier (e.g., an orally suitable carrier or a rectallysuitable carrier, depending on the mode of intended administration). Incertain embodiments, the composition comprises an enteroendocrinepeptide secretion enhancing agent, an absorption inhibitor, a carrier,and one or more of a cholesterol absorption inhibitor, anenteroendocrine peptide, a peptidase inhibitor, a spreading agent, and awetting agent.

In other embodiments, the compositions described herein are administeredorally for non-systemic delivery of the bile salt active component tothe rectum and/or colon, including the sigmoid colon, transverse colon,and/or ascending colon. In specific embodiments, compositions formulatedfor oral administration are, by way of non-limiting example, entericallycoated or formulated oral dosage forms, such as, tablets and/orcapsules. It is to be understood that the terms “subject” and“individual” are utilized interchangeably herein and include, e.g.,humans and human patients in need of treatment.

Absorption Inhibitors

In certain embodiments, the composition described herein as beingformulated for the non-systemic delivery of ASBTI further includes anabsorption inhibitor. As used herein, an absorption inhibitor includesan agent or group of agents that inhibit absorption of a bile acid/salt.

Suitable bile acid absorption inhibitors (also described herein asabsorption inhibiting agents) include, by way of non-limiting example,anionic exchange matrices, polyamines, quaternary amine containingpolymers, quaternary ammonium salts, polyallylamine polymers andcopolymers, colesevelam, colesevelam hydrochloride, CholestaGel(N,N,N-trimethyl-6-(2-propenylamino)-1-hexanaminium chloride polymerwith (chloromethyl)oxirane, 2-propen-1-amine andN-2-propenyl-1-decanamine hydrochloride), cyclodextrins, chitosan,chitosan derivatives, carbohydrates which bind bile acids, lipids whichbind bile acids, proteins and proteinaceous materials which bind bileacids, and antibodies and albumins which bind bile acids. Suitablecyclodextrins include those that bind bile acids/salts such as, by wayof non-limiting example, β-cyclodextrin andhydroxypropyl-β-cyclodextrin. Suitable proteins, include those that bindbile acids/salts such as, by way of non-limiting example, bovine serumalbumin, egg albumin, casein, α^(□)-acid glycoprotein, gelatin, soyproteins, peanut proteins, almond proteins, and wheat vegetableproteins.

In certain embodiments the absorption inhibitor is cholestyramine. Inspecific embodiments, cholestyramine is combined with a bile acid.Cholestyramine, an ion exchange resin, is a styrene polymer containingquaternary ammonium groups crosslinked by divinylbenzene. In otherembodiments, the absorption inhibitor is colestipol. In specificembodiments, colestipol is combined with a bile acid. Colestipol, an ionexchange resin, is a copolymer of diethylenetriamine and1-chloro-2,3-epoxypropane.

In certain embodiments of the compositions and methods described hereinthe ASBTI is linked to an absorption inhibitor, while in otherembodiments the ASBTI and the absorption inhibitor are separatemolecular entities. In specific embodiments the bile acid, bile acidmimic or the modified bile acid is linked to a bile acid adsorptioninhibitor described herein.

Cholesterol Absorption Inhibitors

In certain embodiments, a composition described herein optionallyincludes at least one cholesterol absorption inhibitor. Suitablecholesterol absorption inhibitors include, by way of non-limitingexample, ezetimibe (SCH 58235), ezetimibe analogs, ACT inhibitors,stigmastanyl phosphorylcholine, stigmastanyl phosphorylcholineanalogues, D-lactam cholesterol absorption inhibitors, sulfatepolysaccharides, neomycin, plant sponins, plant sterols, phytostanolpreparation FM-VP4, Sitostanol, D-sitosterol,acyl-CoA:cholesterol-O-acyltransferase (ACAT) inhibitors, Avasimibe,Implitapide, steroidal glycosides and the like. Suitable enzetimibeanalogs include, by way of non-limiting example, SCH 48461, SCH 58053and the like. Suitable ACT inhibitors include, by way of non-limitingexample, trimethoxy fatty acid anilides such as Cl-976,3-[decyldimethylsilyl]-N-[2-(4-methylphenyl)-1-phenylethyl]-propanamide,melinamide and the like. β-lactam cholesterol absorption inhibitorsinclude, by way of non-limiting example,(3R-4S)-1,4-bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone andthe like.

Peptidase Inhibitors

In some embodiments, the compositions described herein optionallyinclude at least one peptidase inhibitor. Such peptidase inhibitorsinclude, but are not limited to, dipeptidyl peptidase-4 inhibitors(DPP-4), neutral endopeptidase inhibitors, and converting enzymeinhibitors. Suitable dipeptidyl peptidase-4 inhibitors (DPP-4) include,by way of non-limiting example, Vildaglipti,2S)-1-{2-[(3-hydroxy-1-adamantyl)amino]acetyl}pyrrolidine-2-carbonitrile,Sitagliptin,(3R)-3-amino-1-[9-(trifluoromethyl)-1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5-trifluorophenyl)butan-1-one, Saxagliptin, and(1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile.Such neutral endopeptidase inhibitors include, but are not limited to,Candoxatrilat and Ecadotril.

Spreading Agents/Wetting Agents

In certain embodiments, the composition described herein optionallycomprises a spreading agent. In some embodiments, a spreading agent isutilized to improve spreading of the composition in the colon and/orrectum. Suitable spreading agents include, by way of non-limitingexample, hydroxyethylcellulose, hydroxypropymethyl cellulose,polyethylene glycol, colloidal silicon dioxide, propylene glycol,cyclodextrins, microcrystalline cellulose, polyvinylpyrrolidone,polyoxyethylated glycerides, polycarbophil, di-n-octyl ethers, Cetiol™OE, fatty alcohol polyalkylene glycol ethers, Aethoxal™ B), 2-ethylhexylpalmitate, Cegesoft™ C 24), and isopropyl fatty acid esters.

In some embodiments, the compositions described herein optionallycomprise a wetting agent. In some embodiments, a wetting agent isutilized to improve wettability of the composition in the colon andrectum. Suitable wetting agents include, by way of non-limiting example,ionic or non-ionic surfactants. In some embodiments, surfactants areselected from, by way of non-limiting example, SLS, poloxamers (e.g.,poloxamer 188), polysorbate (e.g., 20 or 80), stearyl hetanoate,caprylic/capric fatty acid esters of saturated fatty alcohols of chainlength C₁₂-C₁₈, isostearyl diglycerol isostearic acid, sodium dodecylsulphate, isopropyl myristate, isopropyl palmitate, and isopropylmyristate/isopropyl stearate/isopropyl palmitate mixture.

Vitamins

In some embodiments, the methods provided herein further compriseadministering one or more vitamins.

In some embodiments, the vitamin is vitamin A, B1, B2, B3, B5, B6, B7,B9, B12, C, D, E, K, folic acid, pantothenic acid, niacin, riboflavin,thiamine, retinol, beta carotene, pyridoxine, ascorbic acid,cholecalciferol, cyanocobalamin, tocopherols, phylloquinone,menaquinone.

In some embodiments, the vitamin is a fat soluble vitamin such asvitamin A, D, E, K, retinol, beta carotene, cholecalciferol,tocopherols, phylloquinone. In a preferred embodiment, the fat solublevitamin is tocopherol polyethylene glycol succinate (TPGS).

Bile Acid Sequestrants/Binders

In some embodiments, a labile bile acid sequestrant is an enzymedependent bile acid sequestrant. In certain embodiments, the enzyme is abacterial enzyme. In some embodiments, the enzyme is a bacterial enzymefound in high concentration in human colon or rectum relative to theconcentration found in the small intestine. Examples of micro-floraactivated systems include dosage forms comprising pectin, galactomannan,and/or Azo hydrogels and/or glycoside conjugates (e.g., conjugates ofD-galactoside, β-D-xylopyranoside or the like) of the active agent.Examples of gastrointestinal micro-flora enzymes include bacterialglycosidases such as, for example, D-galactosidase, β-D-glucosidase,α-L-arabinofuranosidase, β-D-xylopyranosidase or the like.

In certain embodiments, a labile bile acid sequestrant is a timedependent bile acid sequestrant. In some embodiments, a labile bile acidsequestrant releases a bile acid or is degraded after 1, 2, 3, 4, 5, 6,7, 8, 9, or 10 seconds of sequestration. In some embodiments, a labilebile acid sequestrant releases a bile acid or is degraded after 15, 20,25, 30, 35, 40, 45, 50, or 55 seconds of sequestration. In someembodiments, a labile bile acid sequestrant releases a bile acid or isdegraded after 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 minutes ofsequestration. In some embodiments, a labile bile acid sequestrantreleases a bile acid or is degraded after about 15, 20, 25, 30, 35, 45,50, or 55 minutes of sequestration. In some embodiments, a labile bileacid sequestrant releases a bile acid or is degraded after about 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, or 24 hours of sequestration. In some embodiments, a labile bileacid sequestrant releases a bile acid or is degraded after 1, 2, or 3days of sequestration.

In some embodiments, the labile bile acid sequestrant has a low affinityfor bile acid. In certain embodiments, the labile bile acid sequestranthas a high affinity for a primary bile acid and a low affinity for asecondary bile acid.

In some embodiments, the labile bile acid sequestrant is a pH dependentbile acid sequestrant. In certain embodiments, the pH dependent bileacid sequestrant has a high affinity for bile acid at a pH of 6 or belowand a low affinity for bile acid at a pH above 6. In certainembodiments, the pH dependent bile acid sequestrant has a high affinityfor bile acid at a pH of 6.5 or below and a low affinity for bile acidat a pH above 6.5. In certain embodiments, the pH dependent bile acidsequestrant has a high affinity for bile acid at a pH of 7 or below anda low affinity for bile acid at a pH above 7. In certain embodiments,the pH dependent bile acid sequestrant has a high affinity for bile acidat a pH of 7.1 or below and a low affinity for bile acid at a pH above7.1. In certain embodiments, the pH dependent bile acid sequestrant hasa high affinity for bile acid at a pH of 7.2 or below and a low affinityfor bile acid at a pH above 7.2. In certain embodiments, the pHdependent bile acid sequestrant has a high affinity for bile acid at apH of 7.3 or below and a low affinity for bile acid at a pH above 7.3.In certain embodiments, the pH dependent bile acid sequestrant has ahigh affinity for bile acid at a pH of 7.4 or below and a low affinityfor bile acid at a pH above 7.4. In certain embodiments, the pHdependent bile acid sequestrant has a high affinity for bile acid at apH of 7.5 or below and a low affinity for bile acid at a pH above 7.5.In certain embodiments, the pH dependent bile acid sequestrant has ahigh affinity for bile acid at a pH of 7.6 or below and a low affinityfor bile acid at a pH above 7.6. In certain embodiments, the pHdependent bile acid sequestrant has a high affinity for bile acid at apH of 7.7 or below and a low affinity for bile acid at a pH above 7.7.In certain embodiments, the pH dependent bile acid sequestrant has ahigh affinity for bile acid at a pH of 7.8 or below and a low affinityfor bile acid at a pH above 7.8. In some embodiments, the pH dependentbile acid sequestrant degrades at a pH above 6. In some embodiments, thepH dependent bile acid sequestrant degrades at a pH above 6.5. In someembodiments, the pH dependent bile acid sequestrant degrades at a pHabove 7. In some embodiments, the pH dependent bile acid sequestrantdegrades at a pH above 7.1. In some embodiments, the pH dependent bileacid sequestrant degrades at a pH above 7.2. In some embodiments, the pHdependent bile acid sequestrant degrades at a pH above 7.3. In someembodiments, the pH dependent bile acid sequestrant degrades at a pHabove 7.4. In some embodiments, the pH dependent bile acid sequestrantdegrades at a pH above 7.5. In some embodiments, the pH dependent bileacid sequestrant degrades at a pH above 7.6. In some embodiments, the pHdependent bile acid sequestrant degrades at a pH above 7.7. In someembodiments, the pH dependent bile acid sequestrant degrades at a pHabove 7.8. In some embodiments, the pH dependent bile acid sequestrantdegrades at a pH above 7.9.

In certain embodiments, the labile bile acid sequestrant is lignin or amodified lignin. In some embodiments, the labile bile acid sequestrantis a polycationic polymer or copolymer. In certain embodiments, thelabile bile acid sequestrant is a polymer or copolymer comprising one ormore N-alkenyl-N-alkylamine residues; one or moreN,N,N-trialkyl-N—(N′-alkenylamino)alkyl-azanium residues; one or moreN,N,N-trialkyl-N-alkenyl-azanium residues; one or more alkenyl-amineresidues; or a combination thereof.

In some embodiments, the bile acid binder is cholestyramine, and variouscompositions including cholestyramine, which are described, for example,in U.S. Pat. Nos. 3,383,281; 3,308,020; 3,769,399; 3,846,541; 3,974,272;4,172,120; 4,252,790; 4,340,585; 4,814,354; 4,874,744; 4,895,723;5,695,749; and 6,066, 336. In some embodiments, the bile acid binder ischolestipol or cholesevelam.

Methods

Provided herein, in certain embodiments, are methods for treatingpediatric cholestasis or a pediatric cholestatic liver diseasecomprising non-systemic administration of a therapeutically effectiveamount of an ASBTI. Provided herein, in certain embodiments, are methodsfor treating pediatric cholestasis or a pediatric cholestatic liverdisease comprising contacting the gastrointestinal tract, including thedistal ileum and/or the colon and/or the rectum, of an individual inneed thereof with an ASBTI. Also provided herein are methods forreducing intraenterocyte bile acids, reducing damage to hepatocellularor intestinal architecture caused by cholestasis or a cholestatic liverdisease, of an individual comprising administration of a therapeuticallyeffective amount of an ASBTI to an individual in need thereof.

In some embodiments, provided herein is a method of treating pediatriccholestasis or a pediatric cholestatic liver disease in an individualcomprising delivering to ileum or colon of the individual atherapeutically effective amount of any ASBTI described herein. In someembodiments, provided herein are methods for reducing damage tohepatocellular or intestinal architecture or cells from cholestasis or acholestatic liver disease comprising administration of a therapeuticallyeffective amount of an ASBTI. In certain embodiments, provided hereinare methods for reducing intraenterocyte bile acids/salts comprisingadministration of a therapeutically effective amount of an ASBTI to anindividual in need thereof.

In some embodiments, the methods provide for inhibition of bile saltrecycling upon administration of any of the compounds described hereinto an individual. In some embodiments, an ASBTI described herein issystemically absorbed upon administration. In some embodiments, an ASBTIdescribed herein is not absorbed systemically. In some embodiments, anASBTI herein is administered to the individual orally. In someembodiments, an ASBTI described herein is delivered and/or released inthe distal ileum of an individual.

In certain instances, contacting the distal ileum of a pediatricindividual with an ASBTI (e.g., any ASBTI described herein) inhibitsbile acid reuptake and increases the concentration of bile acids/saltsin the vicinity of L-cells in the distal ileum and/or colon and/orrectum, thereby reducing intraenterocyte bile acids, reducing serumand/or hepatic bile acid levels, reducing overall bile acid load, and/orreducing damage to ileal architecture caused by cholestasis or acholestatic liver disease. Without being limited to any particulartheory, reducing serum and/or hepatic bile acid levels amelioratescholestasis and/or cholestatic disease.

Administration of a compound described herein is achieved in anysuitable manner including, by way of non-limiting example, by oral,enteric, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. Any compound or composition described herein is administered ina method or formulation appropriate to treat a new born or an infant.Any compound or composition described herein is administered in an oralformulation (e.g., solid or liquid) to treat a new born or an infant. Insome embodiments, the pediatric dosage form is selected from a solution,syrup, suspension, elixir, powder for reconstitution as suspension orsolution, dispersible/effervescent tablet, chewable tablet, lollipop,freezer pops, troches, oral thin strips, orally disintegrating tablet,orally disintegrating strip, and sprinkle oral powder or granules. Insome embodiments, a compound or composition described herein isadministered in a method or pediatric dosage form formulationappropriate to treat children. In some embodiments, a compound orcomposition described herein is administered in a method or pediatricdosage form formulation appropriate to treat adolescents. In someembodiments, a compound or composition described herein is administeredin a method or pediatric dosage form formulation appropriate to treat anewborn or an infant. In some embodiments, a compound or compositiondescribed herein is administered in an oral formulation (e.g., solid orliquid) to treat a newborn or an infant. In some embodiments, thepediatric dosage form described herein is administered prior toingestion of food, with food or after ingestion of food.

In certain embodiments, a compound or a composition comprising acompound described herein is administered for prophylactic and/ortherapeutic treatments. In therapeutic applications, the compositionsare administered to an individual already suffering from a disease orcondition, in an amount sufficient to cure or at least partially arrestthe symptoms of the disease or condition. In various instances, amountseffective for this use depend on the severity and course of the diseaseor condition, previous therapy, the individual's health status, weight,and response to the drugs, and the judgment of the treating physician.

In prophylactic applications, compounds or compositions containingcompounds described herein are administered to an individual susceptibleto or otherwise at risk of a particular disease, disorder or condition.In certain embodiments of this use, the precise amounts of compoundadministered depend on the individual's state of health, weight, and thelike. Furthermore, in some instances, when a compound or compositiondescribed herein is administered to an individual, effective amounts forthis use depend on the severity and course of the disease, disorder orcondition, previous therapy, the individual's health status and responseto the drugs, and the judgment of the treating physician.

In certain instances, wherein following administration of a selecteddose of a compound or composition described herein, an individual'scondition does not improve, upon the doctor's discretion theadministration of a compound or composition described herein isoptionally administered chronically, that is, for an extended period oftime, including throughout the duration of the individual's life inorder to ameliorate or otherwise control or limit the symptoms of theindividual's disorder, disease or condition.

In certain embodiments, an effective amount of a given agent variesdepending upon one or more of a number of factors such as the particularcompound, disease or condition and its severity, the identity (e.g.,weight) of the subject or host in need of treatment, and is determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated. In some embodiments, doses administered include those upto the maximum tolerable dose. In some embodiments, doses administeredinclude those up to the maximum tolerable dose by a newborn or aninfant.

In certain embodiments, about 0.001-5000 mg per day, from about0.001-1500 mg per day, about 0.001 to about 100 mg/day, about 0.001 toabout 50 mg/day, or about 0.001 to about 30 mg/day, or about 0.001 toabout 10 mg/day of a compound described herein is administered to anindividual in need thereof. In various embodiments, the desired dose isconveniently presented in a single dose or in divided doses administeredsimultaneously (or over a short period of time) or at appropriateintervals, for example as two, three, four or more sub-doses per day. Invarious embodiments, a single dose is from about 0.001 mg/kg to about500 mg/kg. In various embodiments, a single dose is from about 0.001,0.01, 0.1, 1, or 10 mg/kg to about 10, 50, 100, or 250 mg/kg. In variousembodiments, a single dose of an ASBTI is from about 0.001 mg/kg toabout 100 mg/kg. In various embodiments, a single dose of an ASBTI isfrom about 0.001 mg/kg to about 50 mg/kg. In various embodiments, asingle dose of an ASBTI is from about 0.001 mg/kg to about 10 mg/kg. Invarious embodiments, a single dose of an ASBTI is administered every 6hours, every 12 hours, every 24 hours, every 48 hours, every 72 hours,every 96 hours, every 5 days, every 6 days, or once a week.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion an ASBTI is optionally given continuously; alternatively, thedose of drug being administered is temporarily reduced or temporarilysuspended for a certain length of time (i.e., a “drug holiday”). Thelength of the drug holiday optionally varies between 2 days and 1 year,including by way of example only, 2 days, 3 days, 4 days, 5 days, 6days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dosereduction during a drug holiday includes from 10%-100%, including, byway of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%. In some embodiments thetotal single dose of an ASBTI is in the range described above.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, is reduced, as a function of thesymptoms, to a level at which the improved disease, disorder orcondition is retained. In some embodiments, patients requireintermittent treatment on a long-term basis upon any recurrence ofsymptoms.

In certain instances, there are a large number of variables in regard toan individual treatment regime, and considerable excursions from theserecommended values are considered within the scope described herein.Dosages described herein are optionally altered depending on a number ofvariables such as, by way of non-limiting example, the activity of thecompound used, the disease or condition to be treated, the mode ofadministration, the requirements of the individual subject, the severityof the disease or condition being treated, and the judgment of thepractitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens areoptionally determined by pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. In certainembodiments, data obtained from cell culture assays and animal studiesare used in formulating a range of dosage for use in human. In specificembodiments, the dosage of compounds described herein lies within arange of circulating concentrations that include the ED₅₀ with minimaltoxicity. The dosage optionally varies within this range depending uponthe dosage form employed and the route of administration utilized.

In some embodiments, the systemic exposure of a therapeuticallyeffective amount of any non-systemic ASBTI described herein (e.g., anASBTI that comprises a non-systemic moiety such as L-K or other groupsdescribed herein) is reduced when compared to the systemic exposure of atherapeutically effective amount of any systemically absorbed ASBTI(e.g. Compounds 100A, 100C). In some embodiments, the AUC of atherapeutically effective amount of any non-systemic ASBTI describedherein (e.g., an ASBTI that comprises a non-systemic moiety such as L-Kor other groups described herein) is at least 10%, at least 20%, atleast 30%, at least 40%, at least 50%, at least 60%, at least 70%, atleast 80% or at least 90% reduced when compared to the AUC of anysystemically absorbed ASBTI (e.g. Compounds 100A, 100C).

In some embodiments, the systemic exposure of a therapeuticallyeffective amount of a compound of Formula I that is not systemicallyabsorbed (e.g., a compound of Formula I that comprises a non-systemicmoiety such as L-K or other groups described herein) is reduced whencompared to the systemic exposure of a therapeutically effective amountof Compound 100A. In some embodiments, the AUC of a therapeuticallyeffective amount of a compound of Formula I that is not systemicallyabsorbed (e.g., a compound of Formula I that comprises a non-systemicmoiety such as L-K or other groups described herein) is about 10%, about20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% orabout 90% reduced when compared to the AUC of a therapeuticallyeffective amount of Compound 100A. In some embodiments, the AUC of atherapeutically effective amount of a compound of Formula I that is notsystemically absorbed (e.g., a compound of Formula I that comprises anon-systemic moiety such as L-K or other groups described herein) isabout 50% reduced when compared to the AUC of a therapeuticallyeffective amount of Compound 100A. In other embodiments, the AUC of atherapeutically effective amount of a compound of Formula I that is notsystemically absorbed (e.g., a compound of Formula I that comprises anon-systemic moiety such as L-K or other groups described herein) isabout 75% reduced when compared to the AUC of a therapeuticallyeffective amount of Compound 100A.

In some embodiments, the systemic exposure of a therapeuticallyeffective amount of a compound of Formula II that is not systemicallyabsorbed (e.g., a compound of Formula II that comprises a non-systemicmoiety such as L-K or other groups described herein) is reduced whencompared to the systemic exposure of a therapeutically effective amountof Compound 100A. In some embodiments, the AUC of a therapeuticallyeffective amount of a compound of Formula II that is not systemicallyabsorbed (e.g., a compound of Formula II that comprises a non-systemicmoiety such as L-K or other groups described herein) is about 10%, about20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% orabout 90% reduced when compared to the AUC of a therapeuticallyeffective amount of Compound 100A. In some embodiments, the AUC of atherapeutically effective amount of a compound of Formula II that is notsystemically absorbed (e.g., a compound of Formula II that comprises anon-systemic moiety such as L-K or other groups described herein) isabout 50% reduced when compared to the AUC of a therapeuticallyeffective amount of Compound 100A. In other embodiments, the AUC of atherapeutically effective amount of a compound of Formula II that is notsystemically absorbed (e.g., a compound of Formula II that comprises anon-systemic moiety such as L-K or other groups described herein) isabout 75% reduced when compared to the AUC of a therapeuticallyeffective amount of Compound 100A.

In some embodiments, the systemic exposure of a therapeuticallyeffective amount of a compound of Formula III, IIIA, IIIB or IIIC isreduced when compared to the systemic exposure of a therapeuticallyeffective amount of Compound 100C. In some embodiments, the AUC of atherapeutically effective amount of a compound of Formula III, IIIA,IIIB or IIIC is about 10%, about 20%, about 30%, about 40%, about 50%,about 60%, about 70%, about 80% or about 90% reduced when compared tothe AUC of a therapeutically effective amount of Compound 100C. In someembodiments, the AUC of a therapeutically effective amount of a compoundof Formula III, IIIA, IIIB or IIIC is about 50% reduced when compared tothe AUC of a therapeutically effective amount of Compound 100C. In otherembodiments, the AUC of a therapeutically effective amount of a compoundof Formula III, IIIA, IIIB or IIIC is about 75% reduced when compared tothe AUC of a therapeutically effective amount of Compound 100C.

In some embodiments, the systemic exposure of a therapeuticallyeffective amount of a compound of Formula IV that is not systemicallyabsorbed (e.g., a compound of Formula IV that comprises a non-systemicmoiety such as L-K or other groups described herein) is reduced whencompared to the systemic exposure of a therapeutically effective amountof Compound 100A. In some embodiments, the AUC of a therapeuticallyeffective amount of a compound of Formula IV that is not systemicallyabsorbed (e.g., a compound of Formula I that comprises a non-systemicmoiety such as L-K or other groups described herein) is about 10%₀,about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about80% or about 90% reduced when compared to the AUC of a therapeuticallyeffective amount of Compound 100A. In some embodiments, the AUC of atherapeutically effective amount of a compound of Formula IV that is notsystemically absorbed (e.g., a compound of Formula IV that comprises anon-systemic moiety such as L-K or other groups described herein) isabout 50% reduced when compared to the AUC of a therapeuticallyeffective amount of Compound 100A. In other embodiments, the AUC of atherapeutically effective amount of a compound of Formula IV that is notsystemically absorbed (e.g., a compound of Formula IV that comprises anon-systemic moiety such as L-K or other groups described herein) isabout 75% reduced when compared to the AUC of a therapeuticallyeffective amount of Compound 100A.

In some embodiments, the systemic exposure of a therapeuticallyeffective amount of a compound of Formula V that is not systemicallyabsorbed (e.g., a compound of Formula V that comprises a non-systemicmoiety such as L-K or other groups described herein) is reduced whencompared to the systemic exposure of a therapeutically effective amountof Compound 100A. In some embodiments, the AUC of a therapeuticallyeffective amount of a compound of Formula V that is not systemicallyabsorbed (e.g., a compound of Formula V that comprises a non-systemicmoiety such as L-K or other groups described herein) is about 10%, about20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% orabout 90% reduced when compared to the AUC of a therapeuticallyeffective amount of Compound 100A. In some embodiments, the AUC of atherapeutically effective amount of a compound of Formula I that is notsystemically absorbed (e.g., a compound of Formula V that comprises anon-systemic moiety such as L-K or other groups described herein) isabout 50% reduced when compared to the AUC of a therapeuticallyeffective amount of Compound 100A. In other embodiments, the AUC of atherapeutically effective amount of a compound of Formula I that is notsystemically absorbed (e.g., a compound of Formula V that comprises anon-systemic moiety such as L-K or other groups described herein) isabout 75% reduced when compared to the AUC of a therapeuticallyeffective amount of Compound 100A.

In some embodiments, the systemic exposure of a therapeuticallyeffective amount of a compound of Formula VI or VID that is notsystemically absorbed (e.g., a compound of Formula VI or VID thatcomprises a non-systemic moiety such as L-K or other groups describedherein) is reduced when compared to the systemic exposure of atherapeutically effective amount of Compound 100A. In some embodiments,the AUC of a therapeutically effective amount of a compound of FormulaVI or VID that is not systemically absorbed (e.g., a compound of FormulaVI or VID that comprises a non-systemic moiety such as L-K or othergroups described herein) is about 10%, about 20%, about 30%, about 40%,about 50%, about 60%, about 70%, about 80% or about 90% reduced whencompared to the AUC of a therapeutically effective amount of Compound100A. In some embodiments, the AUC of a therapeutically effective amountof a compound of Formula VI or VID that is not systemically absorbed(e.g., a compound of Formula VI or VID that comprises a non-systemicmoiety such as L-K or other groups described herein) is about 50%reduced when compared to the AUC of a therapeutically effective amountof Compound 100A. In other embodiments, the AUC of a therapeuticallyeffective amount of a compound of Formula I that is not systemicallyabsorbed (e.g., a compound of Formula VI or VID that comprises anon-systemic moiety such as L-K or other groups described herein) isabout 75% reduced when compared to the AUC of a therapeuticallyeffective amount of Compound 100A.

In certain embodiments, the Cmax of a therapeutically effective amountof any non-systemic ASBTI described herein (e.g., an ASBTI thatcomprises a non-systemic moiety such as L-K or other groups describedherein) is at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 70%, at least 80% or at least 90%reduced when compared to the Cmax of any systemically absorbed ASBTI(e.g. Compound 100A).

By way of example, the Cmax of a therapeutically effective amount of acompound of Formula III, IIIA, IIIB or IIIC is about 10%, about 20%,about 30%, about 40%, about 50%, about 60%, about 70%, about 80% orabout 90% reduced when compared to the Cmax of a therapeuticallyeffective amount of Compound 100C. In some embodiments, the Cmax of atherapeutically effective amount of a compound of Formula III, IIIA,IIIB or IIIC is about 25% reduced when compared to the Cmax of atherapeutically effective amount of Compound 100C. In certainembodiments, the Cmax of a therapeutically effective amount of acompound of III, IIIA or IIIB is about 50% reduced when compared to theCmax of a therapeutically effective amount of Compound 100C. In otherembodiments, the Cmax of a therapeutically effective amount of acompound of Formula III, IIIA, IIIB or IIIC is about 75% reduced whencompared to the Cmax of a therapeutically effective amount of Compound100C.

In certain embodiments, the pharmaceutical composition administeredincludes a therapeutically effective amount of a bile salt, a bile acidmimic, or a bile salt mimic, an absorption inhibitor and a carrier(e.g., an orally suitable carrier or a rectally suitable carrier,depending on the mode of intended administration). In certainembodiments, the pharmaceutical composition used or administeredcomprises a bile salt, a bile acid mimic, or a bile salt mimic, anabsorption inhibitor, a carrier, and one or more of a cholesterolabsorption inhibitor, an enteroendocrine peptide, a peptidase inhibitor,a spreading agent, and a wetting agent.

In a specific embodiment, the pharmaceutical composition used to preparea rectal dosage form or administered rectally comprises a bile salt, abile acid mimic, or a bile salt mimic, an absorption inhibitor, arectally suitable carrier, an optional cholesterol absorption inhibitor,an optional enteroendocrine peptide, an optional peptidase inhibitor, anoptional spreading agent, and an optional wetting agent. In certainembodiments, rectally administered compositions evokes an anorectalresponse. In specific embodiments, the anorectal response is an increasein secretion of one or more enteroendocrine by cells (e.g., L-cells) inthe colon and/or rectum (e.g., in the epithelial layer of the colonand/or rectum). In some embodiments, the anorectal response persists forat least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23 or 24 hours. In other embodiments the anorectalresponse persists for a period between 24 hours and 48 hours, while inother embodiments the anorectal response persists for persists for aperiod greater than 48 hours.

In another specific embodiment, the pharmaceutical composition used toprepare an oral dosage form or administered orally comprises a bilesalt, a bile acid mimic, or a bile salt mimic, an absorption inhibitor,an orally suitable carrier, an optional cholesterol absorptioninhibitor, an optional enteroendocrine peptide, an optional peptidaseinhibitor, an optional spreading agent, and an optional wetting agent.In certain embodiments, the orally administered compositions evokes ananorectal response. In specific embodiments, the anorectal response isan increase in secretion of one or more enteroendocrine by cells in thecolon and/or rectum (e.g., in L-cells the epithelial layer of the colonand/or rectum). In some embodiments, the anorectal response persists forat least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, 20, 21, 22, 23 or 24 hours. In other embodiments the anorectalresponse persists for a period between 24 hours and 48 hours, while inother embodiments the anorectal response persists for persists for aperiod greater than 48 hours. Routes of Administration and Dosage

In some embodiments, the compositions described herein and thecompositions administered in the methods described herein are formulatedto inhibit bile acid reuptake, or reduce serum or hepatic bile acidlevels. In certain embodiments, the compositions described herein areformulated for rectal or oral administration. In some embodiments, suchformulations are administered rectally or orally, respectively. In someembodiments, the compositions described herein are combined with adevice for local delivery of the compositions to the rectum and/or colon(sigmoid colon, transverse colon, or ascending colon). In certainembodiments, for rectal administration the composition described hereinare formulated as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas. In someembodiments, for oral administration the compositions described hereinare formulated for oral administration and enteric delivery to thecolon.

In certain embodiments, the compositions or methods described herein arenon-systemic. In some embodiments, compositions described herein deliverthe ASBTI to the distal ileum, colon, and/or rectum and not systemically(e.g., a substantial portion of the enteroendocrine peptide secretionenhancing agent is not systemically absorbed). In some embodiments, oralcompositions described herein deliver the ASBTI to the distal ileum,colon, and/or rectum and not systemically (e.g., a substantial portionof the enteroendocrine peptide secretion enhancing agent is notsystemically absorbed). In some embodiments, rectal compositionsdescribed herein deliver the ASBTI to the distal ileum, colon, and/orrectum and not systemically (e.g., a substantial portion of theenteroendocrine peptide secretion enhancing agent is not systemicallyabsorbed). In certain embodiments, non-systemic compositions describedherein deliver less than 90% w/w of the ASBTI systemically. In certainembodiments, non-systemic compositions described herein deliver lessthan 80% w/w of the ASBTI systemically. In certain embodiments,non-systemic compositions described herein deliver less than 70% w/w ofthe ASBTI systemically. In certain embodiments, non-systemiccompositions described herein deliver less than 60% w/w of the ASBTIsystemically. In certain embodiments, non-systemic compositionsdescribed herein deliver less than 50% w/w of the ASBTI systemically. Incertain embodiments, non-systemic compositions described herein deliverless than 40% w/w of the ASBTI systemically. In certain embodiments,non-systemic compositions described herein deliver less than 30% w/w ofthe ASBTI systemically. In certain embodiments, non-systemiccompositions described herein deliver less than 25% w/w of the ASBTIsystemically. In certain embodiments, non-systemic compositionsdescribed herein deliver less than 20% w/w of the ASBTI systemically. Incertain embodiments, non-systemic compositions described herein deliverless than 15% w/w of the ASBTI systemically. In certain embodiments,non-systemic compositions described herein deliver less than 10% w/w ofthe ASBTI systemically. In certain embodiments, non-systemiccompositions described herein deliver less than 5% w/w of the ASBTIsystemically. In some embodiments, systemic absorption is determined inany suitable manner, including the total circulating amount, the amountcleared after administration, or the like.

In certain embodiments, the compositions and/or formulations describedherein are administered at least once a day. In certain embodiments, theformulations containing the ASBTI are administered at least twice a day,while in other embodiments the formulations containing the ASBTI areadministered at least three times a day. In certain embodiments, theformulations containing the ASBTI are administered up to five times aday. It is to be understood that in certain embodiments, the dosageregimen of composition containing the ASBTI described herein to isdetermined by considering various factors such as the patient's age,sex, and diet.

The concentration of the ASBTI administered in the formulationsdescribed herein ranges from about 1 mM to about 1 M. In certainembodiments the concentration of the ASBTI administered in theformulations described herein ranges from about 1 mM to about 750 mM. Incertain embodiments the concentration of the ASBTI administered in theformulations described herein ranges from about 1 mM to about 500 mM. Incertain embodiments the concentration of the ASBTI administered in theformulations described herein ranges from about 5 mM to about 500 mM. Incertain embodiments the concentration of the ASBTI administered in theformulations described herein ranges from about 10 mM to about 500 mM.In certain embodiments the concentration of the administered in theformulations described herein ranges from about 25 mM to about 500 mM.In certain embodiments the concentration of the ASBTI administered inthe formulations described herein ranges from about 50 mM to about 500mM. In certain embodiments the concentration of the ASBTI administeredin the formulations described herein ranges from about 100 mM to about500 mM. In certain embodiments the concentration of the ASBTIadministered in the formulations described herein ranges from about 200mM to about 500 mM.

In certain embodiments, any composition described herein comprises atherapeutically effective amount (e.g., to treat cholestasis or acholestatic liver disease) of ursodiol. In some embodiments, ursodiolmay be substituted for any other therapeutic bile acid or salt. In someembodiments, compositions described herein comprise or methods describedherein comprise administering about 0.01 mg to about 10 g of ursodiol.In certain embodiments, a composition described herein comprises or amethod described herein comprises administering about 0.1 mg to about500 mg of ursodiol. In certain embodiments, a composition describedherein comprises or a method described herein comprises administeringabout 0.1 mg to about 100 mg of ursodiol. In certain embodiments, acomposition described herein comprises or a method described hereincomprises administering about 0.1 mg to about 50 mg of ursodiol. Incertain embodiments, a composition described herein comprises or amethod described herein comprises administering about 0.1 mg to about 10mg of ursodiol. In certain embodiments, a composition described hereincomprises or a method described herein comprises administering about 0.5mg to about 10 mg of ursodiol. In some embodiments, compositionsdescribed herein comprise or methods described herein compriseadministering about 0.1 mmol to about 1 mol of ursodiol. In certainembodiments, a composition described herein comprises or a methoddescribed herein comprises administering about 0.01 mmol to about 500mmol of ursodiol. In certain embodiments, a composition described hereincomprises or a method described herein comprises administering about 0.1mmol to about 100 mmol of ursodiol. In certain embodiments, acomposition described herein comprises or a method described hereincomprises administering about 0.5 mmol to about 30 mmol of ursodiol. Incertain embodiments, a composition described herein comprises or amethod described herein comprises administering about 0.5 mmol to about20 mmol of ursodiol. In certain embodiments, a composition describedherein comprises or a method described herein comprises administeringabout 1 mmol to about 10 mmol of ursodiol. In certain embodiments, acomposition described herein comprises or a method described hereincomprises administering about 0.01 mmol to about 5 mmol of ursodiol. Incertain embodiments, a composition described herein comprises or amethod described herein comprises administering about 0.1 mmol to about1 mmol of ursodiol. In various embodiments, certain bile acids/saltshave different potencies and dosing is optionally adjusted accordingly.For example, the investigation in TGR5-transfected CHO cells of TGR5agonist potency of natural bile acids/salts indicates the following rankof potency: Lithocholic acid (LCA) >deoxycholic acid (DCA) >murocholicacid (Muro-CA) >lagodeoxycholic acid (lago-DCA) >chenodeoxycholic(CDCA) >cholic acid (CA) >hyodeoxycholic acid (HDCA >ursodeoxycholicacid (UDCA); and assays on TGR5-transfected CHO cells demonstrate thatEC₅₀ (in μM) for UDCA was 36.4, TauroCA (TCA) 4.95 and LCA 0.58.

In certain embodiments, by targeting the distal gastrointestinal tract(e.g., distal ileum, colon, and/or rectum), compositions and methodsdescribed herein provide efficacy (e.g., in reducing microbial growthand/or alleviating symptoms of cholestasis or a cholestatic liverdisease) with a reduced dose of enteroendocrine peptide secretionenhancing agent (e.g., as compared to an oral dose that does not targetthe distal gastrointestinal tract).

Rectal Administration Formulations

The pharmaceutical compositions described herein for the non-systemicdelivery of a compound described herein to the rectum and/or colon areformulated for rectal administration as rectal enemas, rectal foams,rectal gels, and rectal suppositories. The components of suchformulations are described herein. It is to be understood that as usedherein, pharmaceutical compositions and compositions are or comprise theformulations as described herein. In some embodiments, rectalformulations comprise rectal enemas, foams, gels, or suppositories.

In certain embodiments, liquid carrier vehicles or co-solvents in thecompositions and/or formulations described herein include, by way ofnon-limiting example, purified water, propylene glycol, PEG200, PEG300,PEG400, PEG600, polyethyleneglycol, ethanol, 1-propanol, 2-propanol,1-propen-3-ol (allyl alcohol), propylene glycol, glycerol,2-methyl-2-propanol, formamide, methyl formamide, dimethyl formamide,ethyl formamide, diethyl formamide, acetamide, methyl acetamide,dimethyl acetamide, ethyl acetamide, diethyl acetamide, 2-pyrrolidone,N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone, tetramethyl urea,1,3-dimethyl-2-imidazolidinone, propylene carbonate, 1,2-butylenecarbonate, 2,3-butylene carbonate, dimethyl sulfoxide, diethylsulfoxide, hexamethyl phosphoramide, pyruvic aldehyde dimethylacetal,dimethylisosorbide and combinations thereof.

In some embodiments, stabilizers used in compositions and/orformulations described herein include, but are not limited to, partialglycerides of polyoxyethylenic saturated fatty acids.

In certain embodiments, surfactants/emulsifiers used in the compositionsand/or formulations described herein include, by way of non-limitingexample, mixtures of cetostearylic alcohol with sorbitan esterified withpolyoxyethylenic fatty acids, polyoxyethylene fatty ethers,polyoxyethylene fatty esters, fatty acids, sulfated fatty acids,phosphated fatty acids, sulfosuccinates, amphoteric surfactants,non-ionic poloxamers, non-ionic meroxapols, petroleum derivatives,aliphatic amines, polysiloxane derivatives, sorbitan fatty acid esters,laureth-4, PEG-2 dilaurate, stearic acid, sodium lauryl sulfate, dioctylsodium sulfosuccinate, cocoamphopropionate, poloxamer 188, meroxapol258, triethanolamine, dimethicone, polysorbate 60, sorbitanmonostearate, pharmaceutically acceptable salts thereof, andcombinations thereof.

In some embodiments, non-ionic surfactants used in compositions and/orformulations described herein include, by way of non-limiting example,phospholipids, alkyl poly(ethylene oxide), poloxamers (e.g., poloxamer188), polysorbates, sodium dioctyl sulfosuccinate, Brij™-30 (Laureth-4),Brij™-58 (Ceteth-20) and Brij™-78 (Steareth-20), Brij™-721(Steareth-21), Crillet-1 (Polysorbate 20), Crillet-2 (Polysorbate 40),Crillet-3 (Polysorbate 60), Crillet 45 (Polysorbate 80), Myrj-52 (PEG-40Stearate), Myrj-53 (PEG-50 Stearate), Pluronic™ F77 (Poloxamer 217),Pluronic™ F87 (Poloxamer 237), Pluronic™ F98 (Poloxamer 288), Pluronic™L62 (Poloxamer 182), Pluronic™ L64 (Poloxamer 184), Pluronic™ F68(Poloxamer 188), Pluronic™ L81 (Poloxamer 231), Pluronic™ L92 (Poloxamer282), Pluronic™ L101 (Poloxamer 331), Pluronic™ P103 (Poloxamer 333),Pluracare™ F 108 NF (Poloxamer 338), and Pluracare™ F 127 NF (Poloxamer407) and combinations thereof. Pluronic™ polymers are commerciallypurchasable from BASF, USA and Germany.

In certain embodiments, anionic surfactants used in compositions and/orformulations described herein include, by way of non-limiting example,sodium laurylsulphate, sodium dodecyl sulfate (SDS), ammonium laurylsulfate, alkyl sulfate salts, alkyl benzene sulfonate, and combinationsthereof.

In some embodiments, the cationic surfactants used in compositionsand/or formulations described herein include, by way of non-limitingexample, benzalkonium chloride, benzethonium chloride, cetyltrimethylammonium bromide, hexadecyl trimethyl ammonium bromide, otheralkyltrimethylammonium salts, cetylpyridinium chloride, polyethoxylatedtallow and combinations thereof.

In certain embodiments, the thickeners used in compositions and/orformulations described herein include, by way of non-limiting example,natural polysaccharides, semi-synthetic polymers, synthetic polymers,and combinations thereof. Natural polysaccharides include, by way ofnon-limiting example, acacia, agar, alginates, carrageenan, guar,arabic, tragacanth gum, pectins, dextran, gellan and xanthan gums.Semi-synthetic polymers include, by way of non-limiting example,cellulose esters, modified starches, modified celluloses,carboxymethylcellulose, methyl cellulose, ethyl cellulose, hydroxyethylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose.Synthetic polymers include, by way of non-limiting example,polyoxyalkylenes, polyvinyl alcohol, polyacrylamide, polyacrylates,carboxypolymethylene (carbomer), polyvinylpyrrolidone (povidones),polyvinylacetate, polyethylene glycols and poloxamer. Other thickenersinclude, by way of nonlimiting example, polyoxyethyleneglycolisostearate, cetyl alcohol, Polyglycol 300 isostearate, propyleneglycol,collagen, gelatin, and fatty acids (e.g., lauric acid, myristic acid,palmitic acid, stearic acid, palmitoleic acid, linoleic acid, linolenicacid, oleic acid and the like).

In some embodiments, chelating agents used in the compositions and/orformulations described herein include, by way of non-limiting example,ethylenediaminetetraacetic acid (EDTA) or salts thereof, phosphates andcombinations thereof.

In some embodiments, the concentration of the chelating agent or agentsused in the rectal formulations described herein is a suitableconcentration, e.g., about 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5%(w/v).

In some embodiments, preservatives used in compositions and/orformulations described herein include, by way of non-limiting example,parabens, ascorbyl palmitate, benzoic acid, butylated hydroxyanisole,butylated hydroxytoluene, chlorobutanol, ethylenediamine, ethylparaben,methylparaben, butyl paraben, propylparaben, monothioglycerol, phenol,phenylethyl alcohol, propylparaben, sodium benzoate, sodium propionate,sodium formaldehyde sulfoxylate, sodium metabisulfite, sorbic acid,sulfur dioxide, maleic acid, propyl gallate, benzalkonium chloride,benzethonium chloride, benzyl alcohol, chlorhexidine acetate,chlorhexidine gluconate, sorbic acid, potassium sorbitol, chlorbutanol,phenoxyethanol, cetylpyridinium chloride, phenylmercuric nitrate,thimerosol, and combinations thereof.

In certain embodiments, antioxidants used in compositions and/orformulations described herein include, by way of non-limiting example,ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, hypophosphorous acid, monothioglycerol, propyl gallate,sodium ascorbate, sodium sulfite, sodium bisulfite, sodium formaldehydesulfoxylate, potassium metabisulphite, sodium metabisulfite, oxygen,quinones, t-butyl hydroquinone, erythorbic acid, olive (olea eurpaea)oil, pentasodium penetetate, pentetic acid, tocopheryl, tocopherylacetate and combinations thereof.

Pharmaceutically acceptable preservatives include quaternary ammoniumsalts such as benzalkonium chloride, alcohols such as benzyl alcohol,organic acids or salts and derivatives thereof such as benzoic acid,sodium benzoate, sorbic acid, potassium sorbate, propionic acid, sodiumpropionate, parabens such as methyl parahydroxybenzoate, propylparahydroxybenzoate, ethyl parahydroxybenzoate or butylparahydroxybenzoate, aqua conservans; chlorhexidinediacetate,-digluconate. Given the intended use of the presentcomposition, the preservatives are preferably suitable for pediatricuse. Preferred preservatives are parabens such as methylparahydroxybenzoate, propyl parahydroxybenzoate, ethylparahydroxybenzoate or butyl parahydroxybenzoate, in particular methylparahydroxybenzoate or propyl parahydroxybenzoate. The preservatives arepresent in a composition in a concentration in order to providesufficient antimicrobial activity in the preconcentrate composition orin the liquid composition upon reconstitution. Preferably, theconcentration of the preservatives in a resulting reconstituted liquidcomposition ranges up to about 3% (w/w), more preferably up to about2.5% (w/w), more preferably up to about 2% (w/w), depending on theactual preservative being used.

The composition of the present invention may also contain one or moreanti-oxidants, such as, for example, sodium metabisulfite, sodiumbisulfite, sodium sulfite, sodium thiosulfate, ascorbic acid, BHA(butylhydroxyanisol), BHT (butylhydroxytoluene), vitamine E,propylgallate, ascorbyl palmitate, or complex forming agents such asEDTA (ethylenediaminetetraacetic acid), citric acid, tartaric acid,sodium-hexametaphosphate and the like. Given the intended use of thepresent composition, the antioxidants or the complex forming agents arepreferably suitable for pediatric use. Preferred antioxidants are BHA,BHT, vitamin E or propylgallate. In some embodiments, concentration ofthe antioxidant or antioxidants used in the rectal formulationsdescribed herein is sufficient to achieve a desired result, e.g., about0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.4%, or 0.5% (w/v).

The lubricating agents used in compositions and/or formulationsdescribed herein include, by way of non-limiting example, natural orsynthetic fat or oil (e.g., a tris-fatty acid glycerate and the like).In some embodiments, lubricating agents include, by way of non-limitingexample, glycerin (also called glycerine, glycerol, 1,2,3-propanetriol,and trihydroxypropane), polyethylene glycols (PEGs), polypropyleneglycol, polyisobutene, polyethylene oxide, behenic acid, behenylalcohol, sorbitol, mannitol, lactose, polydimethylsiloxane andcombinations thereof.

In certain embodiments, mucoadhesive and/or bioadhesive polymers areused in the compositions and/or formulations described herein as agentsfor inhibiting absorption of the enteroendocrine peptide secretionenhancing agent across the rectal or colonic mucosa. Bioadhesive ormucoadhesive polymers include, by way of non-limiting example,hydroxypropyl cellulose, polyethylene oxide homopolymers, polyvinylether-maleic acid copolymers, methyl cellulose, ethyl cellulose, propylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, carboxymethylcellulose, polycarbophil,polyvinylpyrrolidone, carbopol, polyurethanes, polyethyleneoxide-polypropyline oxide copolymers, sodium carboxymethyl cellulose,polyethylene, polypropylene, lectins, xanthan gum, alginates, sodiumalginate, polyacrylic acid, chitosan, hyaluronic acid and esterderivatives thereof, vinyl acetate homopolymer, calcium polycarbophil,gelatin, natural gums, karaya, tragacanth, algin, chitosan, starches,pectins, and combinations thereof.

In some embodiments, buffers/pH adjusting agents used in compositionsand/or formulations described herein include, by way of non-limitingexample, phosphoric acid, monobasic sodium or potassium phosphate,triethanolamine (TRIS), BICINE, HEPES, Trizma, glycine, histidine,arginine, lysine, asparagine, aspartic acid, glutamine, glutamic acid,carbonate, bicarbonate, potassium metaphosphate, potassium phosphate,monobasic sodium acetate, acetic acid, acetate, citric acid, sodiumcitrate anhydrous, sodium citrate dihydrate and combinations thereof. Incertain embodiments, an acid or a base is added to adjust the pH.Suitable acids or bases include, by way of non-limiting example, HCL,NaOH and KOH.

In certain embodiments, concentration of the buffering agent or agentsused in the rectal formulations described herein is sufficient toachieve or maintain a physiologically desirable pH, e.g., about 0.1%,0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.8%, 0.9%, or 1.0% (w/w).

The tonicity modifiers used in compositions and/or formulationsdescribed herein include, by way of non-limiting example, sodiumchloride, potassium chloride, sodium phosphate, mannitol, sorbitol orglucose.

Pediatric Dosage Formulations and Compositions

Provided herein, in certain embodiments, is a pediatric dosageformulation or composition comprising a therapeutically effective amountof any compound described herein. In certain instances, thepharmaceutical composition comprises an ASBT inhibitor (e.g., any ASBTIdescribed herein).

In certain embodiments, suitable dosage forms include, by way ofnon-limiting example, aqueous or non-aqueous oral dispersions, liquids,gels, syrups, elixirs, slurries, suspensions, solutions, controlledrelease formulations, fast melt formulations, effervescent formulations,lyophilized formulations, chewable tablets, gummy candy, orallydisintegrating tablets, powders for reconstitution as suspension orsolution, sprinkle oral powder or granules, dragees, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate releaseand controlled release formulations. In some embodiments, providedherein is a pharmaceutical composition wherein the pediatric dosage formis selected from a solution, syrup, suspension, elixir, powder forreconstitution as suspension or solution, dispersible/effervescenttablet, chewable tablet, gummy candy, lollipop, freezer pops, troches,oral thin strips, orally disintegrating tablet, orally disintegratingstrip, sachet, and sprinkle oral powder or granules.

In another aspect, provide herein is a pharmaceutical compositionwherein at least one excipient is a flavoring agent or a sweetener. Insome embodiments, provided herein is a coating. In some embodiments,provided herein is a taste-masking technology selected from coating ofdrug particles with a taste-neutral polymer by spray-drying, wetgranulation, fluidized bed, and microencapsulation; coating with moltenwaxes of a mixture of molten waxes and other pharmaceutical adjuvants;entrapment of drug particles by complexation, flocculation orcoagulation of an aqueous polymeric dispersion; adsorption of drugparticles on resin and inorganic supports; and solid dispersion whereina drug and one or more taste neutral compounds are melted and cooled, orco-precipitated by a solvent evaporation. In some embodiments, providedherein is a delayed or sustained release formulation comprising drugparticles or granules in a rate controlling polymer or matrix.

Suitable sweeteners include sucrose, glucose, fructose or intensesweeteners, i.e. agents with a high sweetening power when compared tosucrose (e.g. at least 10 times sweeter than sucrose). Suitable intensesweeteners comprise aspartame, saccharin, sodium or potassium or calciumsaccharin, acesulfame potassium, sucralose, alitame, xylitol, cyclamate,neomate, neohesperidine dihydrochalcone or mixtures thereof, thaumatin,palatinit, stevioside, rebaudioside, Magnasweet®. The totalconcentration of the sweeteners may range from effectively zero to about300 mg/ml based on the liquid composition upon reconstitution.

In order to increase the palatability of the liquid composition uponreconstitution with an aqueous medium, one or more taste-making agentsmay be added to the composition in order to mask the taste of the ASBTinhibitor. A taste-masking agent can be a sweetener, a flavoring agentor a combination thereof. The taste-masking agents typically provide upto about 0.1% or 5% by weight of the total pharmaceutical composition.In a preferred embodiment of the present invention, the compositioncontains both sweetener(s) and flavor(s).

A flavoring agent herein is a substance capable of enhancing taste oraroma of a composition. Suitable natural or synthetic flavoring agentscan be selected from standard reference books, for example Fenaroli'sHandbook of Flavor Ingredients, 3rd edition (1995). Non-limitingexamples of flavoring agents and/or sweeteners useful in theformulations described herein, include, e.g., acacia syrup, acesulfameK, alitame, anise, apple, aspartame, banana, Bavarian cream, berry,black currant, butterscotch, calcium citrate, camphor, caramel, cherry,cherry cream, chocolate, cinnamon, bubble gum, citrus, citrus punch,citrus cream, cotton candy, cocoa, cola, cool cherry, cool citrus,cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose, fruitpunch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup, grape,grapefruit, honey, isomalt, lemon, lime, lemon cream, monoammoniumglyrrhizinate (MagnaSweet®), maltol, mannitol, maple, marshmallow,menthol, mint cream, mixed berry, neohesperidine DC, neotame, orange,pear, peach, peppermint, peppermint cream, Prosweet® Powder, raspberry,root beer, rum, saccharin, safrole, sorbitol, spearmint, spearmintcream, strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine,thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,wintergreen, xylitol, or any combination of these flavoring ingredients,e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon,chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus,orange-cream, vanilla-mint, and mixtures thereof. Flavoring agents canbe used singly or in combinations of two or more. In some embodiments,the aqueous liquid dispersion comprises a sweetening agent or flavoringagent in a concentration ranging from about 0.001% to about 5.0% thevolume of the aqueous dispersion. In one embodiment, the aqueous liquiddispersion comprises a sweetening agent or flavoring agent in aconcentration ranging from about 0.001% to about 1.0% the volume of theaqueous dispersion. In another embodiment, the aqueous liquid dispersioncomprises a sweetening agent or flavoring agent in a concentrationranging from about 0.005% to about 0.5% the volume of the aqueousdispersion. In yet another embodiment, the aqueous liquid dispersioncomprises a sweetening agent or flavoring agent in a concentrationranging from about 0.01% to about 1.0% the volume of the aqueousdispersion. In yet another embodiment, the aqueous liquid dispersioncomprises a sweetening agent or flavoring agent in a concentrationranging from about 0.01% to about 0.5% the volume of the aqueousdispersion.

In certain embodiments, pharmaceutical compositions are formulated in aconventional manner using one or more physiologically acceptablecarriers including, e.g., excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which are suitablefor pharmaceutical use. In certain embodiments, proper formulation isdependent upon the route of administration chosen. A summary ofpharmaceutical compositions described herein is found, for example, inRemington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

A pharmaceutical composition, as used herein, refers to a mixture of acompound described herein, such as, for example, a compound of FormulaI-VI, with other chemical components, such as carriers, stabilizers,diluents, dispersing agents, suspending agents, thickening agents,and/or excipients. In certain instances, the pharmaceutical compositionfacilitates administration of the compound to an individual or cell. Incertain embodiments of practicing the methods of treatment or useprovided herein, therapeutically effective amounts of compoundsdescribed herein are administered in a pharmaceutical composition to anindividual having a disease, disorder, or condition to be treated. Inspecific embodiments, the individual is a human. As discussed herein,the compounds described herein are either utilized singly or incombination with one or more additional therapeutic agents.

In certain embodiments, the pharmaceutical formulations described hereinare administered to an individual in any manner, including one or moreof multiple administration routes, such as, by way of non-limitingexample, oral, parenteral (e.g., intravenous, subcutaneous,intramuscular), intranasal, buccal, topical, rectal, or transdermaladministration routes.

In certain embodiments, a pharmaceutical compositions described hereinincludes one or more compound described herein as an active ingredientin free-acid or free-base form, or in a pharmaceutically acceptable saltform. In some embodiments, the compounds described herein are utilizedas an N-oxide or in a crystalline or amorphous form (i.e., a polymorph).In some situations, a compound described herein exists as tautomers. Alltautomers are included within the scope of the compounds presentedherein. In certain embodiments, a compound described herein exists in anunsolvated or solvated form, wherein solvated forms comprise anypharmaceutically acceptable solvent, e.g., water, ethanol, and the like.The solvated forms of the compounds presented herein are also consideredto be described herein.

A “carrier” includes, in some embodiments, a pharmaceutically acceptableexcipient and is selected on the basis of compatibility with compoundsdescribed herein, such as, compounds of any of Formula I-VI, and therelease profile properties of the desired dosage form. Exemplary carriermaterials include, e.g., binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, diluents, and the like. See, e.g.,Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton,Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. 1975;Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999).

Moreover, in certain embodiments, the pharmaceutical compositionsdescribed herein are formulated as a dosage form. As such, in someembodiments, provided herein is a dosage form comprising a compounddescribed herein, suitable for administration to an individual. Incertain embodiments, suitable dosage forms include, by way ofnon-limiting example, aqueous oral dispersions, liquids, gels, syrups,elixirs, slurries, suspensions, solid oral dosage forms, aerosols,controlled release formulations, fast melt formulations, effervescentformulations, lyophilized formulations, tablets, powders, pills,dragees, capsules, delayed release formulations, extended releaseformulations, pulsatile release formulations, multiparticulateformulations, and mixed immediate release and controlled releaseformulations.

In certain aspects, the composition or formulation containing one ormore compounds described herein is orally administered for localdelivery of an ASBTI, or a compound described herein to the colon and/orrectum. Unit dosage forms of such compositions include a pill, tablet orcapsules formulated for enteric delivery to colon. In certainembodiments, such pills, tablets or capsule contain the compositionsdescribed herein entrapped or embedded in microspheres. In someembodiments, microspheres include, by way of non-limiting example,chitosan microcores HPMC capsules and cellulose acetate butyrate (CAB)microspheres. In certain embodiments, oral dosage forms are preparedusing conventional methods known to those in the field of pharmaceuticalformulation. For example, in certain embodiments, tablets aremanufactured using standard tablet processing procedures and equipment.An exemplary method for forming tablets is by direct compression of apowdered, crystalline or granular composition containing the activeagent(s), alone or in combination with one or more carriers, additives,or the like. In alternative embodiments, tablets are prepared usingwet-granulation or dry-granulation processes. In some embodiments,tablets are molded rather than compressed, starting with a moist orotherwise tractable material.

In certain embodiments, tablets prepared for oral administration containvarious excipients, including, by way of non-limiting example, binders,diluents, lubricants, disintegrants, fillers, stabilizers, surfactants,preservatives, coloring agents, flavoring agents and the like. In someembodiments, binders are used to impart cohesive qualities to a tablet,ensuring that the tablet remains intact after compression. Suitablebinder materials include, by way of non-limiting example, starch(including corn starch and pregelatinized starch), gelatin, sugars(including sucrose, glucose, dextrose and lactose), polyethylene glycol,propylene glycol, waxes, and natural and synthetic gums, e.g., acaciasodium alginate, polyvinylpyrrolidone, cellulosic polymers (includinghydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethyl cellulose, hydroxyethyl cellulose, and the like),Veegum, and combinations thereof. In certain embodiments, diluents areutilized to increase the bulk of the tablet so that a practical sizetablet is provided. Suitable diluents include, by way of non-limitingexample, dicalcium phosphate, calcium sulfate, lactose, cellulose,kaolin, mannitol, sodium chloride, dry starch, powdered sugar andcombinations thereof. In certain embodiments, lubricants are used tofacilitate tablet manufacture; examples of suitable lubricants include,by way of non-limiting example, vegetable oils such as peanut oil,cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma,glycerin, magnesium stearate, calcium stearate, stearic acid andcombinations thereof. In some embodiments, disintegrants are used tofacilitate disintegration of the tablet, and include, by way ofnon-limiting example, starches, clays, celluloses, algins, gums,crosslinked polymers and combinations thereof. Fillers include, by wayof non-limiting example, materials such as silicon dioxide, titaniumdioxide, alumina, talc, kaolin, powdered cellulose and microcrystallinecellulose, as well as soluble materials such as mannitol, urea, sucrose,lactose, dextrose, sodium chloride and sorbitol. In certain embodiments,stabilizers are used to inhibit or retard drug decomposition reactionsthat include, by way of example, oxidative reactions. In certainembodiments, surfactants are anionic, cationic, amphoteric or nonionicsurface active agents.

In some embodiments, ASBTIs, or other compounds described herein areorally administered in association with a carrier suitable for deliveryto the distal gastrointestinal tract (e.g., distal ileum, colon, and/orrectum).

In certain embodiments, a composition described herein comprises anASBTI, or other compounds described herein in association with a matrix(e.g., a matrix comprising hypermellose) that allows for controlledrelease of an active agent in the distal part of the ileum and/or thecolon. In some embodiments, a composition comprises a polymer that is pHsensitive (e.g., a MMX™ matrix from Cosmo Pharmaceuticals) and allowsfor controlled release of an active agent in the distal part of theileum. Examples of such pH sensitive polymers suitable for controlledrelease include and are not limited to polyacrylic polymers (e.g.,anionic polymers of methacrylic acid and/or methacrylic acid esters,e.g., Carbopol polymers) that comprise acidic groups (e.g., —COOH,—SO₃H) and swell in basic pH of the intestine (e.g., pH of about 7 toabout 8). In some embodiments, a composition suitable for controlledrelease in the distal ileum comprises microparticulate active agent(e.g., micronized active agent). In some embodiments, anon-enzymatically degrading poly(dl-lactide-co-glycolide) (PLGA) core issuitable for delivery of an enteroendocrine peptide secretion enhancingagent (e.g., bile acid) to the distal ileum. In some embodiments, adosage form comprising an enteroendocrine peptide secretion enhancingagent (e.g., bile acid) is coated with an enteric polymer (e.g.,Eudragit® S-100, cellulose acetate phthalate, polyvinylacetatephthalate, hydroxypropylmethylcellulose phthalate, anionic polymers ofmethacrylic acid, methacrylic acid esters or the like) for site specificdelivery to the distal ileum and/or the colon. In some embodiments,bacterially activated systems are suitable for targeted delivery to thedistal part of the ileum. Examples of micro-flora activated systemsinclude dosage forms comprising pectin, galactomannan, and/or Azohydrogels and/or glycoside conjugates (e.g., conjugates ofD-galactoside, β-D-xylopyranoside or the like) of the active agent.Examples of gastrointestinal micro-flora enzymes include bacterialglycosidases such as, for example, D-galactosidase, β-D-glucosidase,α-L-arabinofuranosidase, β-D-xylopyranosidase or the like.

The pharmaceutical composition described herein optionally include anadditional therapeutic compound described herein and one or morepharmaceutically acceptable additives such as a compatible carrier,binder, filling agent, suspending agent, flavoring agent, sweeteningagent, disintegrating agent, dispersing agent, surfactant, lubricant,colorant, diluent, solubilizer, moistening agent, plasticizer,stabilizer, penetration enhancer, wetting agent, anti-foaming agent,antioxidant, preservative, or one or more combination thereof. In someaspects, using standard coating procedures, such as those described inRemington's Pharmaceutical Sciences, 20th Edition (2000), a film coatingis provided around the formulation of the compound of Formula I. In oneembodiment, a compound described herein is in the form of a particle andsome or all of the particles of the compound are coated. In certainembodiments, some or all of the particles of a compound described hereinare microencapsulated. In some embodiments, the particles of thecompound described herein are not microencapsulated and are uncoated.

In further embodiments, a tablet or capsule comprising an ASBTI or othercompounds described herein is film-coated for delivery to targeted siteswithin the gastrointestinal tract. Examples of enteric film coatsinclude and are not limited to hydroxypropylmethylcellulose, polyvinylpyrrolidone, hydroxypropyl cellulose, polyethylene glycol 3350, 4500,8000, methyl cellulose, pseudo ethylcellulose, amylopectin and the like.

Solid Dosage Forms for Pediatric Administration

Solid dosage forms for pediatric administration of the present inventioncan be manufactured by standard manufacturing techniques. Non-limitingexamples of oral solid dosage forms for pediatric administration aredescribed below.

Effervescent Compositions

The effervescent compositions of the invention may be prepared accordingto techniques well-known in the art of pharmacy.

Effervescent formulations contain and effervescent couple of a basecomponent and an acid component, which components reach in the presenceof water to generate a gas. In some embodiments, the base component maycomprise, for example, an alkali metal or alkaline earth metalcarbonate, or bicarbonate. The acid component may comprise, for example,an aliphatic carboxylic acid or a salt thereof, such as citric acid. Thebase and acid components may each independently constitute, for example,25% to 55% (w/w) of the effervescent composition. The ratio of acidcomponent to base component may be within the range of 1:2 to 2:1.

The effervescent compositions of the invention may be formulated usingadditional pharmaceutically acceptable carriers or excipients asappropriate. For example, one or more taste masking agents may be used.Dyes may also be used, as pediatric patients often prefer colorfulpharmaceutical combinations. The compositions may take the form of, forexample, tablets, granules or powders, granules or powders presented ina sachet.

Chewable Tablets

The chewable tablets of the invention may be prepared according totechniques well-known in the art of pharmacy.

Chewable tablets are tablets that are intended to disintegrate in themouth under the action of chewing or sucking and where, in consequence,the active ingredient has greater opportunity to come into contact withthe bitter-taste receptors on the tongue.

One method of overcoming this issue is to absorb the active ingredientonto a suitable substrate. This approach is described in U.S. Pat. No.4,647,459.

Another approach involves forming the active ingredient into anaggregate along with a pre-swelled substantially anhydrous hydrocolloid.The hydrocolloid absorbs saliva and acquires a slippery texture whichenables it to lubricate the particles of aggregate and mask the taste ofthe active ingredient. This approach is described in European patentapplication 0190826.

Another approach involves employing a water-insoluble hygroscopicexcipient such as microcrystalline cellulose. This approach is describedin U.S. Pat. No. 5,275,823.

In addition to the above approaches, the chewable tablets of the presentinvention can also contain other stand tabletting excipients such as adisintegrant and a taste-masking agent.

Orodispersible Tablets

The orodispersible tablets of the invention may be prepared according totechniques well-known in the art of pharmacy.

In orodispersible tablets of the invention, the excipient mixtures issuch as to provide it with a disintegration rate so that itsdisintegration in the buccal cavity occurs in an extremely short timeand especially shorter than sixty seconds. In some embodiments, theexcipient mixture is characterized by the fact that the active substanceis in the form of coated or non-coated microcrystals of microgranules.In some embodiments, the orodispersible tablet comprises one or severaldisintegrating agents of the carboxymethylcellulose type or insolublereticulated PVP type, one or several swelling agents which may comprisea carboxymethylcellulose, a starch, a modified starch, or amicrocrystalline cellulose or optionally a direct compression sugar.

Powders for Reconstitution

The powder for reconstitution pharmaceutical compositions of theinvention may be prepared according to techniques well-known in the artof pharmacy.

In some embodiments, the powder for reconstitution compositions of theinvention comprise an effective amount of at least one internaldehydrating agent. The internal dehydrating agent can enhance thestability of the powder. In some embodiments, the internal dehydratingagent is magnesium citrate or disodium carbonate. In some embodiments,the powder composition comprises a pharmaceutically acceptable diluents,such as sucrose, dextrose, mannitol, xylitol, or lactose.

Powder compositions of the inventions may be placed in sachets orbottles for contemporaneous dissolution or for short term storage inliquid form (e.g. 7 days).

Gummy Candies

The gummy candies of the invention may be prepared according totechniques well-known in the art of pharmacy.

Traditional gummy candy is made from a gelatin base. Gelatin gives thecandy its elasticity, the desired chewy consistency, and a longer shelflife. In some embodiments, the gummy candy pharmaceutical composition ofthe invention includes a binding agent, a sweetener, and an activeingredient.

In some embodiments, the binding agent is a pectin gel, gelatin, foodstarch, or any combination thereof.

In some embodiments, the gummy candy comprises sweeteners, a bindingagent, natural and/or artificial flavors and colors and preservatives.In some embodiments, the gummy candy comprises glucose syrup, naturalcane juice, gelatin, citric acid, lactic acid, natural colors, naturalflavors, fractionated coconut oil, and carnauba wax.

Liquid Dosage Forms

The pharmaceutical liquid dosage forms of the invention may be preparedaccording to techniques well-known in the art of pharmacy.

A solution refers to a liquid pharmaceutical formulation wherein theactive ingredient is dissolved in the liquid. Pharmaceutical solutionsof the invention include syrups and elixers. A suspension refers to aliquid pharmaceutical formulation wherein the active ingredient is in aprecipitate in the liquid.

In a liquid dosage form, it is desirable to have a particular pH and/orto be maintained within a specific pH range. In order to control the pH,a suitable buffer system can be used. In addition, the buffer systemshould have sufficient capacity to maintain the desired pH range.Examples of the buffer system useful in the present invention includebut are not limited to, citrate buffers, phosphate buffers, or any othersuitable buffer known in the art. Preferably the buffer system includesodium citrate, potassium citrate, sodium bicarbonate, potassiumbicarbonate, sodium dihydrogen phosphate and potassium dihydrogenphosphate, etc. The concentration of the buffer system in the finalsuspension varies according to factors such as the strength of thebuffer system and the pH/pH ranges required for the liquid dosage form.In one embodiment, the concentration is within the range of 0.005 to 0.5w/v % in the final liquid dosage form.

The pharmaceutical composition comprising the liquid dosage form of thepresent invention can also include a suspending/stabilizing agent toprevent settling of the active material. Over time the settling couldlead to caking of the active to the inside walls of the product pack,leading to difficulties with redispersion and accurate dispensing.Suitable stabilising agents include but are not limited to, thepolysaccharide stabilizers such as xanthan, guar and tragacanth gums aswell as the cellulose derivatives HPMC (hydroxypropyl methylcellulose),methyl cellulose and Avicel RC-591 (microcrystalline cellulose/sodiumcarboxymethyl cellulose). In another embodiment, polyvinylpyrrolidone(PVP) can also be used as a stabilizing agent.

In addition to the aforementioned components, the ASBTI oral suspensionform can also optionally contain other excipients commonly found inpharmaceutical compositions such as alternative solvents, taste-maskingagents, antioxidants, fillers, acidifiers, enzyme inhibitors and othercomponents as described in Handbook of Pharmaceutical Excipients, Roweet al., Eds., 4^(th) Edition, Pharmaceutical Press (2003), which ishereby incorporated by reference.

Addition of an alternative solvent may help increase solubility of anactive ingredient in the liquid dosage form, and consequently theabsorption and bioavailability inside the body of a subject. Preferablythe alternative solvents include methanol, ethanol or propylene glycoland the like.

In another aspect, the present invention provides a process forpreparing the liquid dosage form. The process comprises steps ofbringing ASBTI or its pharmaceutically acceptable salts thereof intomixture with the components including glycerol or syrup or the mixturethereof, a preservative, a buffer system and a suspending/stabilizingagent, etc., in a liquid medium. In general, the liquid dosage form isprepared by uniformly and intimately mixing these various components inthe liquid medium. For example, the components such as glycerol or syrupor the mixture thereof, a preservative, a buffer system and asuspending/stabilizing agent, etc., can be dissolved in water to formthe aqueous solution, then the active ingredient can be then dispersedin the aqueous solution to form a suspension.

In some embodiments, the liquid dosage form provided herein can be in avolume of between 5 ml to 50 ml. In some embodiments, the liquid dosageform provided herein can be in a volume of between 5 ml to 40 ml. Insome embodiments, the liquid dosage form provided herein can be in avolume of between 5 ml to 30 ml. In some embodiments, the liquid dosageform provided herein can be in a volume of between 5 ml to 20 ml. Insome embodiments, the liquid dosage form provided herein can be in avolume of between 10 ml to 30 ml. In some embodiments, the ASBTI can bein an amount ranging from about 0.001% to 90% of the total volume. Insome embodiments, the ASBTI can be in an amount ranging from about 0.01%to 80% of the total volume. In some embodiments, the ASBTI can be in anamount ranging from about 0.1% to 70% of the total volume. In someembodiments, the ASBTI can be in an amount ranging from about 1% to 60%of the total volume. In some embodiments, the ASBTI can be in an amountranging from about 1% to 50% of the total volume. In some embodiments,the ASBTI can be in an amount ranging from about 1% to 40% of the totalvolume. In some embodiments, the ASBTI can be in an amount ranging fromabout 1% to 30% of the total volume. In some embodiments, the ASBTI canbe in an amount ranging from about 1% to 20% of the total volume. Insome embodiments, the ASBTI can be in an amount ranging from about 1% to10% of the total volume. In some embodiments, the ASBTI can be in anamount ranging from about 5% to 70% of the total volume. In someembodiments, the ASBTI can be in an amount ranging from about 5% to 60%of the total volume. In some embodiments, the ASBTI can be in an amountranging from about 5% to 50% of the total volume. In some embodiments,the ASBTI can be in an amount ranging from about 5% to 40% of the totalvolume. In some embodiments, the ASBTI can be in an amount ranging fromabout 5% to 30% of the total volume. In some embodiments, the ASBTI canbe in an amount ranging from about 5% to 20% of the total volume. Insome embodiments, the ASBTI can be in an amount ranging from about 5% to10% of the total volume. In some embodiments, the ASBTI can be in anamount ranging from about 10% to 50% of the total volume. In someembodiments, the ASBTI can be in an amount ranging from about 10% to 40%of the total volume. In some embodiments, the ASBTI can be in an amountranging from about 10% to 30% of the total volume. In some embodiments,the ASBTI can be in an amount ranging from about 10% to 20% of the totalvolume. In one embodiment, the resulted liquid dosage form can be in aliquid volume of 10 ml to 30 ml, preferably 20 ml, and the activeingredient can be in an amount ranging from about 0.001 mg/ml to about16 mg/ml, or from about 0.025 mg/ml to about 8 mg/ml, or from about 0.1mg/ml to about 4 mg/ml, or about 0.25 mg/ml, or about 0.5 mg/ml, orabout 1 mg/ml, or about 2 mg/ml, or about 4 mg/ml, or about 5 mg/ml, orabout 8 mg/ml, or about 10 mg/ml, or about 12 mg/ml, or about 14 mg/mlor about 16 mg/ml.

Bile Acid Sequestrant

In certain embodiments, an oral formulation for use in any methoddescribed herein is, e.g., an ASBTI in association with a labile bileacid sequestrant. A labile bile acid sequestrant is a bile acidsequestrant with a labile affinity for bile acids. In certainembodiments, a bile acid sequestrant described herein is an agent thatsequesters (e.g., absorbs or is charged with) bile acid, and/or thesalts thereof.

In specific embodiments, the labile bile acid sequestrant is an agentthat sequesters (e.g., absorbs or is charged with) bile acid, and/or thesalts thereof, and releases at least a portion of the absorbed orcharged bile acid, and/or salts thereof in the distal gastrointestinaltract (e.g., the colon, ascending colon, sigmoid colon, distal colon,rectum, or any combination thereof). In certain embodiments, the labilebile acid sequestrant is an enzyme dependent bile acid sequestrant. Inspecific embodiments, the enzyme is a bacterial enzyme. In someembodiments, the enzyme is a bacterial enzyme found in highconcentration in human colon or rectum relative to the concentrationfound in the small intestine. Examples of micro-flora activated systemsinclude dosage forms comprising pectin, galactomannan, and/or Azohydrogels and/or glycoside conjugates (e.g., conjugates ofD-galactoside, β-D-xylopyranoside or the like) of the active agent.Examples of gastrointestinal micro-flora enzymes include bacterialglycosidases such as, for example, D-galactosidase, β-D-glucosidase,α-L-arabinofuranosidase, β-D-xylopyranosidase or the like. In someembodiments, the labile bile acid sequestrant is a time dependent bileacid sequestrant (i.e., the bile acid sequesters the bile acid and/orsalts thereof and after a time releases at least a portion of the bileacid and/or salts thereof). In some embodiments, a time dependent bileacid sequestrant is an agent that degrades in an aqueous environmentover time. In certain embodiments, a labile bile acid sequestrantdescribed herein is a bile acid sequestrant that has a low affinity forbile acid and/or salts thereof, thereby allowing the bile acidsequestrant to continue to sequester bile acid and/or salts thereof inan environ where the bile acids/salts and/or salts thereof are presentin high concentration and release them in an environ wherein bileacids/salts and/or salts thereof are present in a lower relativeconcentration. In some embodiments, the labile bile acid sequestrant hasa high affinity for a primary bile acid and a low affinity for asecondary bile acid, allowing the bile acid sequestrant to sequester aprimary bile acid or salt thereof and subsequently release a secondarybile acid or salt thereof as the primary bile acid or salt thereof isconverted (e.g., metabolized) to the secondary bile acid or saltthereof. In some embodiments, the labile bile acid sequestrant is a pHdependent bile acid sequestrant. In some embodiments, the pH dependentbile acid sequestrant has a high affinity for bile acid at a pH of 6 orbelow and a low affinity for bile acid at a pH above 6. In certainembodiments, the pH dependent bile acid sequestrant degrades at a pHabove 6.

In some embodiments, labile bile acid sequestrants described hereininclude any compound, e.g., a macro-structured compound, that cansequester bile acids/salts and/or salts thereof through any suitablemechanism. For example, in certain embodiments, bile acid sequestrantssequester bile acids/salts and/or salts thereof through ionicinteractions, polar interactions, static interactions, hydrophobicinteractions, lipophilic interactions, hydrophilic interactions, stericinteractions, or the like. In certain embodiments, macrostructuredcompounds sequester bile acids/salts and/or sequestrants by trapping thebile acids/salts and/or salts thereof in pockets of the macrostructuredcompounds and, optionally, other interactions, such as those describedabove. In some embodiments, bile acid sequestrants (e.g., labile bileacid sequestrants) include, by way of non-limiting example, lignin,modified lignin, polymers, polycationic polymers and copolymers,polymers and/or copolymers comprising anyone one or more ofN-alkenyl-N-alkylamine residues; one or moreN,N,N-trialkyl-N—(N′-alkenylamino)alkyl-azanium residues; one or moreN,N,N-trialkyl-N-alkenyl-azanium residues; one or more alkenyl-amineresidues; or a combination thereof, or any combination thereof.

Covalent Linkage of the Drug with a Carrier

In some embodiments, strategies used for colon targeted deliveryinclude, by way of non-limiting example, covalent linkage of the ASBTIor other compounds described herein to a carrier, coating the dosageform with a pH-sensitive polymer for delivery upon reaching the pHenvironment of the colon, using redox sensitive polymers, using a timereleased formulation, utilizing coatings that are specifically degradedby colonic bacteria, using bioadhesive system and using osmoticallycontrolled drug delivery systems.

In certain embodiments of such oral administration of a compositioncontaining an ASBTI or other compounds described herein involvescovalent linking to a carrier wherein upon oral administration thelinked moiety remains intact in the stomach and small intestine. Uponentering the colon the covalent linkage is broken by the change in pH,enzymes, and/or degradation by intestinal microflora. In certainembodiments, the covalent linkage between the ASBTI and the carrierincludes, by way of non-limiting example, azo linkage, glycosideconjugates, glucuronide conjugates, cyclodextrin conjugates, dextranconjugates, and amino-acid conjugates (high hydrophilicity and longchain length of the carrier amino acid).

Coating with Polymers: pH-Sensitive Polymers

In some embodiments, the oral dosage forms described herein are coatedwith an enteric coating to facilitate the delivery of an ASBTI or othercompounds described herein to the colon and/or rectum. In certainembodiments, an enteric coating is one that remains intact in the low pHenvironment of the stomach, but readily dissolved when the optimumdissolution pH of the particular coating is reached which depends uponthe chemical composition of the enteric coating. The thickness of thecoating will depend upon the solubility characteristics of the coatingmaterial. In certain embodiments, the coating thicknesses used in suchformulations described herein range from about 25 μm to about 200 μm.

In certain embodiments, the compositions or formulations describedherein are coated such that an ASBTI or other compounds described hereinof the composition or formulation is delivered to the colon and/orrectum without absorbing at the upper part of the intestine. In aspecific embodiment, specific delivery to the colon and/or rectum isachieved by coating of the dosage form with polymers that degrade onlyin the pH environment of the colon. In alternative embodiments, thecomposition is coated with an enteric coat that dissolves in the pH ofthe intestines and an outer layer matrix that slowly erodes in theintestine. In some of such embodiments, the matrix slowly erodes untilonly a core composition comprising an enteroendocrine peptide secretionenhancing agent (and, in some embodiments, an absorption inhibitor ofthe agent) is left and the core is delivered to the colon and/or rectum.

In certain embodiments, pH-dependent systems exploit the progressivelyincreasing pH along the human gastrointestinal tract (GIT) from thestomach (pH 1-2 which increases to 4 during digestion), small intestine(pH 6-7) at the site of digestion and it to 7-8 in the distal ileum. Incertain embodiments, dosage forms for oral administration of thecompositions described herein are coated with pH-sensitive polymer(s) toprovide delayed release and protect the enteroendocrine peptidesecretion enhancing agents from gastric fluid. In certain embodiments,such polymers are be able to withstand the lower pH values of thestomach and of the proximal part of the small intestine, butdisintegrate at the neutral or slightly alkaline pH of the terminalileum and/or ileocecal junction. Thus, in certain embodiments, providedherein is an oral dosage form comprising a coating, the coatingcomprising a pH-sensitive polymer. In some embodiments, the polymersused for colon and/or rectum targeting include, by way of non-limitingexample, methacrylic acid copolymers, methacrylic acid and methylmethacrylate copolymers, Eudragit L100, Eudragit S100, Eudragit L-30D,Eudragit FS-30D, Eudragit L100-55, polyvinylacetate phthalate,hyrdoxypropyl ethyl cellulose phthalate, hyrdoxypropyl methyl cellulosephthalate 50, hyrdoxypropyl methyl cellulose phthalate 55, celluloseacetate trimelliate, cellulose acetate phthalate and combinationsthereof.

In certain embodiments, oral dosage forms suitable for delivery to thecolon and/or rectum comprise a coating that has a biodegradable and/orbacteria degradable polymer or polymers that are degraded by themicroflora (bacteria) in the colon. In such biodegradable systemssuitable polymers include, by way of non-limiting example, azo polymers,linear-type-segmented polyurethanes containing azo groups,polygalactomannans, pectin, glutaraldehyde crosslinked dextran,polysaccharides, amylose, guar gum, pectin, chitosan, inulin,cyclodextrins, chondroitin sulphate, dextrans, locust bean gum,chondroitin sulphate, chitosan, poly (-caprolactone), polylactic acidand poly(lactic-co-glycolic acid).

In certain embodiments of such oral administration of compositionscontaining one or more ASBTIs or other compounds described herein, thecompositions are delivered to the colon without absorbing at the upperpart of the intestine by coating of the dosage forms with redoxsensitive polymers that are degraded by the microflora (bacteria) in thecolon. In such biodegradable systems such polymers include, by way ofnon-limiting example, redox-sensitive polymers containing an azo and/ora disulfide linkage in the backbone.

In some embodiments, compositions formulated for delivery to the colonand/or rectum are formulated for time-release. In some embodiments, timerelease formulations resist the acidic environment of the stomach,thereby delaying the release of the enteroendocrine peptide secretionenhancing agents until the dosage form enters the colon and/or rectum.

In certain embodiments the time released formulations described hereincomprise a capsule (comprising an enteroendocrine peptide secretionenhancing agent and an optional absorption inhibitor) with hydrogelplug. In certain embodiments, the capsule and hydrogel plug are coveredby a water-soluble cap and the whole unit is coated with an entericpolymer. When the capsule enters the small intestine the enteric coatingdissolves and the hydrogels plug swells and dislodges from the capsuleafter a period of time and the composition is released from the capsule.The amount of hydrogel is used to adjust the period of time to therelease the contents.

In some embodiments, provided herein is an oral dosage form comprising amulti-layered coat, wherein the coat comprises different layers ofpolymers having different pH-sensitivities. As the coated dosage formmoves along GIT the different layers dissolve depending on the pHencountered. Polymers used in such formulations include, by way ofnon-limiting example, polymethacrylates with appropriate pH dissolutioncharacteristics, Eudragit® RL and Eudragit® RS (inner layer), andEudragit® FS (outer layer). In other embodiments the dosage form is anenteric coated tablets having an outer shell of hydroxypropylcelluloseor hydroxypropylmethylcellulose acetate succinate (HPMCAS).

In some embodiments, provided herein is an oral dosage form thatcomprises coat with cellulose butyrate phthalate, cellulose hydrogenphthalate, cellulose proprionate phthalate, polyvinyl acetate phthalate,cellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcelluloseacetate, dioxypropyl methylcellulose succinate, carboxymethylethylcellulose, hydroxypropyl methylcellulose acetate succinate,polymers and copolymers formed from acrylic acid, methacrylic acid, andcombinations thereof.

Combination Therapy

In certain instances, provided herein are combination compositionsand/or therapies comprising any compound described herein and anadditional therapeutic agent. In some embodiments, the additionaltherapeutic agent is a L-cell endocrine peptide enhancer. In someinstances, the L-cell endocrine peptide enhancer is a GLP-2 enhancer. Insome embodiments, the GLP-2 enhancer is GLP-2, a GLP-2 secretionenhancer, a GLP-2 degradation inhibitor, the like, or a combinationthereof. In certain instances, enhanced GLP-2 concentration providesregeneration of intestinal lining and/or heals injury to thegastrointestinal structures and/or reduces induction of cytokines and/orenhances the adaptive process, attenuates intestinal injury, reducesbacterial translocation, inhibits the release of free radical oxygen, orany combination thereof. In some instances, the L-cell endocrine peptideenhancer is a PYY enhancer. In some instances, the L-cell endocrinepeptide enhancer is an oxyntomodulin enhancer. In some instances,enhanced PYY or oxyntomodulin secretion heals injury to intestine causedby an cholestasis or a cholestatic liver disease.

TGR5 Receptor Modulators

In some instances, the additional therapeutic agent modulates bile acidreceptors in the gastrointestinal lumen. In some embodiments, theadditional therapeutic agent agonizes or partially agonizes bile acidreceptors (e.g., TGR5 receptors or Famesoid-X receptors) in thegastrointestinal tract. In some embodiments, the additional therapeuticagent is a bile acid analog. In certain instances the additionaltherapeutic agent is a TGR5 agonist. In certain instances,administration of a TGR5 agonist in combination with any of thecompounds described herein enhances the secretion of enteroendocrinepeptides from L-cells. TGR5 modulators (e.g., agonists) include, and arenot limited to, the compounds described in, WO 2008/091540, WO2008/067219 and U.S. Appl. No. 2008/0221161.

Enteroendocrine Peptides

In some embodiments, the additional therapeutic agent is anenteroendocrine peptide. In some embodiments, enteroendocrine peptidesheals injury to intestine or liver due to a cholestatic liver disease.Examples of enteroendocrine peptides that are administered as additionaltherapeutic agents include and are not limited to GLP-1 or GLP-1 analogssuch as Taspoglutide® (Ipsen), or the like.

Combination Therapy with Fat Soluble Vitamins

In some embodiments, the methods provided herein further compriseadministering one or more vitamins. In some embodiments, the vitamin isvitamin A, B1, B2, B3, B5, B6, B7, B9, B12, C, D, E, K, folic acid,pantothenic acid, niacin, riboflavin, thiamine, retinol, beta carotene,pyridoxine, ascorbic acid, cholecalciferol, cyanocobalamin, tocopherols,phylloquinone, menaquinone.

In some embodiments, the vitamin is a fat soluble vitamin such asvitamin A, D, E, K, retinol, beta carotene, cholecalciferol,tocopherols, phylloquinone. In a preferred embodiment, the fat solublevitamin is tocopherol polyethylene glycol succinate (TPGS).

Combination Therapy with Partial External Biliary Diversion (PEBD)

In some embodiments, the methods provided herein further comprise usingpartial external biliary diversion as a treatment for patients who havenot yet developed cirrhosis. This treatment helps reduce the circulationof bile acids/salts in the liver in order to reduce complications andprevent the need for early transplantation in many patients.

This surgical technique involves isolating a segment of intestine 10 cmlong for use as a biliary conduit (a channel for the passage of bile)from the rest of the intestine. One end of the conduit is attached tothe gallbladder and the other end is brought out to the skin to form astoma (a surgically constructed opening to permit the passage of waste).Partial external biliary diversion may be used for patients who areunresponsive to all medical therapy, especially older, larger patients.This procedure may not be of help to young patients such as infants.Partial external biliary diversion may decrease the intensity of theitching and abnormally low levels of cholesterol in the blood.

Combination Therapy with ASBTI and Ursodiol

In some embodiments, an ASBTI is administered in combination withursodiol or ursodeoxycholic acid, chenodeoxycholic acid, cholic acid,taurocholic acid, ursocholic acid, glycocholic acid, glycodeoxycholicacid, taurodeoxycholic acid, taurocholate, glycochenodeoxycholic acid,tauroursodeoxycholic acid. In some instances an increase in theconcentration of bile acids/salts in the distal intestine inducesintestinal regeneration, attenuating intestinal injury, reducingbacterial translocation, inhibiting the release of free radical oxygen,inhibiting production of proinflammatory cytokines, or any combinationthereof or any combination thereof.

An ASBTI and a second active ingredient are used such that thecombination is present in a therapeutically effective amount. Thattherapeutically effective amount arises from the use of a combination ofan ASBTI and the other active ingredient (e.g., ursodiol) wherein eachis used in a therapeutically effective amount, or by virtue of additiveor synergistic effects arising from the combined use, each can also beused in a subclinical therapeutically effective amount, i.e., an amountthat, if used alone, provides for reduced effectiveness for thetherapeutic purposes noted herein, provided that the combined use istherapeutically effective. In some embodiments, the use of a combinationof an ASBTI and any other active ingredient as described hereinencompasses combinations where the ASBTI or the other active ingredientis present in a therapeutically effective amount, and the other ispresent in a subclinical therapeutically effective amount, provided thatthe combined use is therapeutically effective owing to their additive orsynergistic effects. As used herein, the term “additive effect”describes the combined effect of two (or more) pharmaceutically activeagents that is equal to the sum of the effect of each agent given alone.A syngergistic effect is one in which the combined effect of two (ormore) pharmaceutically active agents is greater than the sum of theeffect of each agent given alone. Any suitable combination of an ASBITwith one or more of the aforementioned other active ingredients andoptionally with one or more other pharmacologically active substances iscontemplated as being within the scope of the methods described herein.

In some embodiments, the particular choice of compounds depends upon thediagnosis of the attending physicians and their judgment of thecondition of the individual and the appropriate treatment protocol. Thecompounds are optionally administered concurrently (e.g.,simultaneously, essentially simultaneously or within the same treatmentprotocol) or sequentially, depending upon the nature of the disease,disorder, or condition, the condition of the individual, and the actualchoice of compounds used. In certain instances, the determination of theorder of administration, and the number of repetitions of administrationof each therapeutic agent during a treatment protocol, is based on anevaluation of the disease being treated and the condition of theindividual.

In some embodiments, therapeutically-effective dosages vary when thedrugs are used in treatment combinations. Methods for experimentallydetermining therapeutically-effective dosages of drugs and other agentsfor use in combination treatment regimens are described in theliterature.

In some embodiments of the combination therapies described herein,dosages of the co-administered compounds vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein is optionally administered either simultaneously with thebiologically active agent(s), or sequentially. In certain instances, ifadministered sequentially, the attending physician will decide on theappropriate sequence of therapeutic compound described herein incombination with the additional therapeutic agent.

The multiple therapeutic agents (at least one of which is a therapeuticcompound described herein) are optionally administered in any order oreven simultaneously. If simultaneously, the multiple therapeutic agentsare optionally provided in a single, unified form, or in multiple forms(by way of example only, either as a single pill or as two separatepills). In certain instances, one of the therapeutic agents isoptionally given in multiple doses. In other instances, both areoptionally given as multiple doses. If not simultaneous, the timingbetween the multiple doses is any suitable timing, e.g, from more thanzero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations arealso envisioned (including two or more compounds described herein).

In certain embodiments, a dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, is modified inaccordance with a variety of factors. These factors include the disorderfrom which the subject suffers, as well as the age, weight, sex, diet,and medical condition of the subject. Thus, in various embodiments, thedosage regimen actually employed varies and deviates from the dosageregimens set forth herein.

In some embodiments, the pharmaceutical agents which make up thecombination therapy described herein are provided in a combined dosageform or in separate dosage forms intended for substantially simultaneousadministration. In certain embodiments, the pharmaceutical agents thatmake up the combination therapy are administered sequentially, witheither therapeutic compound being administered by a regimen calling fortwo-step administration. In some embodiments, two-step administrationregimen calls for sequential administration of the active agents orspaced-apart administration of the separate active agents. In certainembodiments, the time period between the multiple administration stepsvaries, by way of non-limiting example, from a few minutes to severalhours, depending upon the properties of each pharmaceutical agent, suchas potency, solubility, bioavailability, plasma half-life and kineticprofile of the pharmaceutical agent.

In certain embodiments, provided herein are combination therapies. Incertain embodiments, the compositions described herein comprise anadditional therapeutic agent. In some embodiments, the methods describedherein comprise administration of a second dosage form comprising anadditional therapeutic agent. In certain embodiments, combinationtherapies the compositions described herein are administered as part ofa regimen. Therefore, additional therapeutic agents and/or additionalpharmaceutical dosage form can be applied to a patient either directlyor indirectly, and concomitantly or sequentially, with the compositionsand formulations described herein.

Kits

In another aspect, provided herein are kits containing a device forrectal administration pre-filled a pharmaceutical composition describedherein. In certain embodiments, kits contain a device for oraladministration and a pharmaceutical composition as described herein. Incertain embodiments the kits includes prefilled sachet or bottle fororal administration, while in other embodiments the kits includeprefilled bags for administration of rectal gels. In certain embodimentsthe kits includes prefilled syringes for administration of oral enemas,while in other embodiments the kits include prefilled syringes foradministration of rectal gels. In certain embodiments the kits includesprefilled pressurized cans for administration of rectal foams.

Release in Distal Ileum and/or Colon

In certain embodiments, a dosage form comprises a matrix (e.g., a matrixcomprising hypermellose) that allows for controlled release of an activeagent in the distal jejunum, proximal ileum, distal ileum and/or thecolon. In some embodiments, a dosage form comprises a polymer that is pHsensitive (e.g., a MMX™ matrix from Cosmo Pharmaceuticals) and allowsfor controlled release of an active agent in the ileum and/or the colon.Examples of such pH sensitive polymers suitable for controlled releaseinclude and are not limited to polyacrylic polymers (e.g., anionicpolymers of methacrylic acid and/or methacrylic acid esters, e.g.,Carbopol® polymers) that comprise acidic groups (e.g., —COOH, —SO₃H) andswell in basic pH of the intestine (e.g., pH of about 7 to about 8). Insome embodiments, a dosage form suitable for controlled release in thedistal ileum comprises microparticulate active agent (e.g., micronizedactive agent). In some embodiments, a non-enzymatically degradingpoly(dl-lactide-co-glycolide) (PLGA) core is suitable for delivery of anASBTI to the distal ileum. In some embodiments, a dosage form comprisingan ASBTI is coated with an enteric polymer (e.g., Eudragit® S-100,cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropylmethylcellulose phthalate, anionic polymers of methacrylicacid, methacrylic acid esters or the like) for site specific delivery tothe ileum and/or the colon. In some embodiments, bacterially activatedsystems are suitable for targeted delivery to the ileum. Examples ofmicro-flora activated systems include dosage forms comprising pectin,galactomannan, and/or Azo hydrogels and/or glycoside conjugates (e.g.,conjugates of D-galactoside, β-D-xylopyranoside or the like) of theactive agent. Examples of gastrointestinal micro-flora enzymes includebacterial glycosidases such as, for example, D-galactosidase,β-D-glucosidase, α-L-arabinofuranosidase, β-D-xylopyranosidase or thelike.

The pharmaceutical solid dosage forms described herein optionallyinclude an additional therapeutic compound described herein and one ormore pharmaceutically acceptable additives such as a compatible carrier,binder, filling agent, suspending agent, flavoring agent, sweeteningagent, disintegrating agent, dispersing agent, surfactant, lubricant,colorant, diluent, solubilizer, moistening agent, plasticizer,stabilizer, penetration enhancer, wetting agent, anti-foaming agent,antioxidant, preservative, or one or more combination thereof. In someaspects, using standard coating procedures, such as those described inRemington's Pharmaceutical Sciences, 20th Edition (2000), a film coatingis provided around the formulation of the compound of Formula I-VI. Inone embodiment, a compound described herein is in the form of a particleand some or all of the particles of the compound are coated. In certainembodiments, some or all of the particles of a compound described hereinare microencapsulated. In some embodiments, the particles of thecompound described herein are not microencapsulated and are uncoated.

An ASBT inhibitor (e.g., a compound of Formula I-VI) is used in thepreparation of medicaments for the prophylactic and/or therapeutictreatment of cholestasis or a cholestatic liver disease. A method fortreating any of the diseases or conditions described herein in anindividual in need of such treatment, involves administration ofpharmaceutical compositions containing at least one ASBT inhibitordescribed herein, or a pharmaceutically acceptable salt,pharmaceutically acceptable N-oxide, pharmaceutically active metabolite,pharmaceutically acceptable prodrug, or pharmaceutically acceptablesolvate thereof, in therapeutically effective amounts to saidindividual.

Screening Process

Provided in certain embodiments herein are processes and kits foridentifying compounds suitable for treating cholestasis or a cholestaticliver disease. In certain embodiments, provided herein are assays foridentifying compounds that selectively inhibits the ASBT by:

-   -   a. providing cells that are a model of intestinal cells;    -   b. contacting the cells with a compound (e.g., a compound as        described herein);    -   c. detecting or measuring the effect of the compound on the        inhibition of ASBT activity.

In certain embodiments, provided herein are assays for identifyingcompounds that are non-systemic compounds by

-   -   a. providing cells that are a model of intestinal permeability        (e.g., Caco-2 cells);    -   b. culturing the cells as a monolayer on semi-permeable plastic        supports that are fitted into the wells of multi-well culture        plates;    -   c. contacting the apical or basolateral surface of the cells        with a compound (e.g., a compound as described herein) and        incubating for a suitable length of time;    -   d. detecting or measuring the concentration of the compound on        both sides of the monolayer by liquid-chromatography-mass        spectrometry (LC-MS) and computing intestinal permeability of        the compound.

In certain embodiments, non-systemic compounds are identified bysuitable parallel artificial membrane permeability assays (PAMPA).

In certain embodiments, non-systemic compounds are identified by use ofisolated vascular-perfused gut preparations.

In certain embodiments, provided herein are assays for identifyingcompounds that inhibit recycling of bile acid salts by

-   -   a. providing cells that are a model of intestinal cells with        apical bile acid transporters (e.g., BHK cells, CHO cells);    -   b. incubating the cells with a compound (e.g., a compound as        described herein) and/or a radiolabeled bile acid (e.g., ¹⁴C        taurocholate) for a suitable length of time;    -   c. washing the cells with a suitable buffer (e.g. phosphate        buffered saline);    -   d. detecting or measuring the residual concentration of the        radiolabeled bile acid in the cells.

EXAMPLES Example 1: Synthesis of1-phenethyl-1-((1,4-diazabicyclo[2.2.2]octanyl)pentyl)imidodicarbonimidicdiamide, iodide salt

Step 1: Synthesis of 5-(1,4-diazabicyclo[2.2.2]octanyl)-1-iodo pentane,iodide salt

1,4-diazabicyclo[2.2.2]octane is suspended in THF. Diiodopentane isadded dropwise and the mixture is refluxed overnight. The reactionmixture is filtered.

Step 2: Synthesis ofN-phenethyl-5-(1,4-diazabicyclo[2.2.2]octanyl)-1-iodo pentane, iodidesalt

5-(1,4-diazabicyclo[2.2.2]octanyl)-1-iodo pentane, iodide salt issuspended in acetonitrile. Phenethylamine is added dropwise and themixture is refluxed overnight. The reaction mixture is filtered.

Step 3: Synthesis of1-phenethyl-1-((1,4-diazabicyclo[2.2.2]octanyl)pentyl)imidodicarbonimidicdiamide, iodide salt

N-phenethyl-5-(1,4-diazabicyclo[2.2.2]octanyl)-1-iodo pentane, iodidesalt is heated with dicyanodiamide in n-butanol for 4 h. The reactionmixture is concentrated under reduced pressure.

The compounds in Table 1 are prepared using methods as described herein,and using appropriate starting materials.

TABLE 1 Compound No. Structure 1

2

3

4

5

6

7

8

9

10

11

Example 2: In Vitro Assay for Inhibition of ASBT-Mediated Bile AcidUptake

Baby hamster kidney (BHK) cells are transfected with cDNA of human ASBT.The cells are seeded in 96-well tissue culture plates at 60,000cells/well. Assays are run within 24 hours of seeding.

On the day of the assay the cell monolayer is washed with 100 mL ofassay buffer. The test compound is added to each well along with 6 mM[¹⁴C] taurocholate in assay buffer (final concentration of 3 mM [¹⁴C]taurocholate in each well). The cell cultures are incubated for 2 h at37° C. The wells are washed with PBS. Scintillation counting fluid isadded to each well, the cells are shaken for 30 minutes prior tomeasuring amount of radioactivity in each well. A test compound that hassignificant ASBT inhibitory activity provides an assay wherein lowlevels of radioactivity are observed in the cells.

Example 3: In Vitro Assay for Secretion of GLP-2

Human NCI-H716 cells are used as a model for L-cells. Two days beforeeach assay experiment, cells are seeded in 12-well culture plates coatedwith Matrigel® to induce cell adhesion. On the day of the assay, cellsare washed with buffer. The cells are incubated for 2 hours with mediumalone, or with test compound. The extracellular medium is assayed forthe presence of GLP-2. Peptides in the medium are collected by reversephase adsorption and the extracts are stored until assay. The presenceof GLP-2 is assayed using ELISA. The detection of increased levels ofGLP-2 in a well containing a test compound identifies the test compoundas a compound that can enhance GLP-2 secretions from L-cells.

Example 4: In Vivo Bioavailability Assay

The test compounds are solubilized in saline solutions. Sprague Dawleyrats are dosed at 2-10 mg/kg body weight by iv and oral dosing.Peripheral blood samples are taken from the femoral artery at selectedtime periods up to 8 hours. Plasma concentrations of the compounds aredetermined by quantitative HPLC and/or mass spectrometry. Clearance andAUC values are determined for the compounds.

For oral dosing, bioavailability is calculated by also drawing plasmasamples from the portal vein. Cannulae are inserted in the femoralartery and the hepatic portal vein to obtain estimates of totalabsorption of drug without first-pass clearance in the liver. Thefraction absorbed (F) is calculated by

F=AUC _(po) /AUC _(iv)

Example 5: Assay to Determine Ileal Intraenterocyte and Luminal BileAcid Levels

Ileal luminal bile acid levels in SD rats are determined by flushing a3-cm section of distal ileum with sterile, cold PBS. After flushing withadditional PBS, the same section of ileum is weighed and thenhomogenized in fresh PBS for determination of interenterocyte bile acidlevels. A LC/MS/MS system is used to evaluate cholic acid, DCA, LCA,chnodeoxycholic acid, and ursodeoxycholic acid levels.

Example 6: Animal to Determine Effect of Therapy on Cholestasis or aCholestatic Liver Disease

Mdr2 knock out mouse model of cholestasis or a cholestatic liver diseaseinduced rats (by carbon tetrachloride/phenobarbital) is used to testcompositions described herein. The animals are orally administered acomposition comprising an ASBTI such as 100B, 264W94; SD5613;SAR548304B; SA HMR1741;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine.

Cholestasis or cholestatic liver disease is quantitated by total bileacid and bilirubin in serum versus that in control mice/ratsadministered with placebo. Serum bile acids/salts are determined byELISA with specific antibodies for cholic and CCDCA. Serum bilirubinlevels are determined by automated routine assays. Alternatively, liversof the mice can be harvested and pathology of the hepatocellular damagecan be measured.

Example 7 Investigation of Orally Delivered LUM001 and1-[4-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]4-aza-1-azoniabicyclo[2.2.2]octanemethane sulfonate (Compound 100B) on Plasma GLP-2 Levels in Normal Rats

12-week-old male HSD rats are fasted for 16 h and given oral dose of 0,3, 30, 100 mg/kg of the ASBTIs LUM001 or1-[4-[4-[(4R,5R)-3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl]phenoxy]butyl]4-aza-1-azoniabicyclo[2.2.2]octanemethane sulfonate (Synthesized by Nanosyn Inc., CA, USA) in a mixture ofvaline-pyrrolidine in water (n=5 per group). Blood samples in volume of0.6 ml for each time point are taken from the caudal vein with aheparinized capillary tube 0, 1, 3 and 5 h after the administration ofcompounds and plasma GLP-2 level are determined. Aprotinin and 10 μl ofDPP-IV inhibitor per ml of blood are used for blood sample preservationduring 10 min centrifugation and for storage at −70° C. or below. GLP-2(Active pM) is tested by any commercially available ELISA kits.

Example 8: Tablet Formulation

10 kg of a compound of Formula I-VI is first screened through a suitablescreen (e.g. 500 micron). 25 kg Lactose monohydrate, 8 kghydroxypropylmethyl cellulose, the screened compound of Formula I-VI and5 kg calcium hydrogen phosphate (anhydrous) are then added to a suitableblender (e.g. a tumble mixer) and blended. The blend is screened througha suitable screen (e.g. 500 micron) and reblended. About 50% of thelubricant (2.5 kg, magnesium stearate) is screened, added to the blendand blended briefly. The remaining lubricant (2 kg, magnesium stearate)is screened, added to the blend and blended briefly. The granules arescreened (e.g. 200 micron) to obtain granulation particles of thedesired size. In some embodiments, the granules are optionally coatedwith a drug release controlling polymer such as polyvinylpyrrolidine,hydroxypropylcellulose, hydroxypropylmethyl cellulose, methyl cellulose,or a methacrylic acid copolymer, to provide an extended releaseformulation. The granules are filled in gelatin capsules.

Example 9: Pediatric Formulation

Disintegrating Tablet Formulation

The following example describes a large scale preparation (100 kg) of anASBTI compound of Formula I-VI (e.g., LUM-001 or LUM-002).

Active ingredient (LUM-001)  2.5 kg Lactose monohydrate NF 47.5 kgPregelatinized starch NF   18 kg microcrystalline cellulose NF   17 kgcroscarmellose sodium NF  6.5 kg povidone K29/32 USP  8.5 kg  100 kg

Pass ASBTI (2.5 kg), lactose monohydrate NF (47.5 kg), pregelatinizedstarch NF (18 kg), microcrystalline cellulose NF (17 kg), croscarmellosesodium NF (6.5 kg) and povidone K29/32 USP (8.5 kg) through a #10 meshscreen. Add the screened material to a 600 Collette mixer. Mix for 6minutes at low speed, without chopper. Add the direct blend mixture fromthe previous step to a 20-cubic foot V-shell PK blender (Model C266200).Pass magnesium stearate NF (0.5 to 1 kg) through a 10 mesh screen into aproperly prepared container. Add approximately half of the magnesiumstearate to each side of the PK blender and blend for 5 minutes. Add theblended mixture from the previous step to Kikusui tablet press forcompression into tablets. The compression equipment can be outfitted tomake tooling for 50 mg tablet, 75 mg tablet and 100 mg tablet.

Example 10: Effervescent Tablet

The active ingredient, anhydrous monosodium citrate, sodium bicarbonateand aspartame are mixed together and granulated by the addition of asolution of the polyvinylpyrrolidone in the alcohol. The granulesobtained after mixing are dried and passed through a calibrator, and theresulting granules are then mixed with the sodium benzoate andflavorings. The granulated material is compressed into tablets using analternative machine fitted with 20 mm punches.

A rotative machine fitted with 20 mm punches may also be used fortabletting.

Active ingredient  4.4 mg Sodium bicarbonate 20.5 mg Monosodium citrateanhydrous 20.6 mg Aspartame 1.25 mg Polyvinylpyrrolidone  1.0 mg Sodiumbenzoate  1.5 mg Orange flavor IFF 29G44  0.5 mg Lemon flavor IFF 29M1940.25 mg Absolute alcohol for granulation

Example 11: Chewable Tablet

A 40% (w/w) solution of the Eudragit E100 in ethanol was added withmixing to the active ingredient and blended until granules were formed.The resulting granules were dried and then sieved through a 16 meshscreen.

Active ingredient  4.0 mg Eudragit E100  0.6 mg Sorbitol: DirectCompression Grade 18.8 mg Lactose: Direct Compression Grade 15.6 mgCroscarmellose Sodium Type A  1.2 mg Aspartame  0.3 mg Aniseed flavoring 0.6 mg Butterscotch flavoring  0.6 mg Magnesium Stearate  0.6 mgMicrocrystalline Cellulose  4.7 mg (Avicel PH102)   47 mg

The active ingredient granules and extragranular excipients were putinto a cone blender and mixed thoroughly. The resulting mix wasdischarged from the blender and compressed on a suitable rotary tabletpress fitted with the appropriate punches.

Example 12: Orodispersible Tablet

The active ingredient is introduced in a fluidized air bed installationand a solution of ethylcellulose in ethanol is sprayed thereon.

The excipients are sieved and the coated active ingredient ishomogenized with the excipients in a mixing apparatus under dryconditions.

Distribution and tabletting are carried out on a compressing machineequipped with punches having a diameter equal to 16 mm and a radius ofcurvature equal to 20 mm.

The pressure is 15 kNewtons±1. The hardness of the thus obtained tabletsis 50 Newtons±5. The time of disintegration in the mouth is from 15 to20 seconds.

Active ingredient (with ethylcellulose)  4.0 mg Reticulatedpolyvinylpyrrolidone 20.0 mg Starch   40 mg Sweetener  1.0 mg Flavor 1.0 mg Magnesium stearate  1.0 mg 67.0 mg

Example 13: Powder Formulation

A pulverulent mixture of active ingredient and polyvidone (5 parts byweight) is granulated with 7% of purified water (weight/weight).

A premix is prepared with the following constituents: carbasalatecalcium (amount corresponding to parts by weight of acetylsalicylicacid); anhydrous citric acid (168 parts by weight); sodium bicarbonate(232 parts by weight); lactose (1500 parts by weight); magnesium citrate(180 parts by weight); potassium benzoate (250 parts by weight). Thepremix is then dry compacted.

The pulverulent active ingredient mixture and the dry compacted premix,and the following compounds: aspartame and artificial vanilla flavoring,which are in powder form, are mixed.

The mixture of powders can be packaged directly in sachets.

Active ingredient  4.0 mg Polividone  0.2 mg Carbasalate calcium  2.6 mgCitic acid  6.7 mg Sodium bicarbonate  9.3 mg Lactose   60 mg Magnesiumcitrate  7.2 mg Potassium benzoate   10 mg  100 mg

Example 14: Gummy Candy

About 50 lbs of warm water is mixed with about 50 lbs of gelatin in themixing tank, to form 100 lbs of gelling compound having a homogeneous50/50 blend of water and gelatin. About 0.1% to 10% of sodium bisulfateby weight is added to the gelling compound to reduce the pH of thegelling compound to about 3.5.

In the mixing weigh vessel, the gelling compound is mixed with about 6lbs of water, 38.3 lbs of sucrose, and 50 lbs of corn syrup to form thecandy slurry. If the active ingredient is not a heat sensitive drug, theactive ingredient is added to the candy slurry prior to cooking. About0.1% sodium citrate by weight is be added to the candy slurry tomaintain the pH of the slurry at about 3.0 to 3.5.

Next, the candy slurry is heated to a temperature of about 180° F. priorto being passed through the storage buffer tank, to the static cooker.In the static cooker, the candy slurry is heated to a temperature ofabout 240° F. to 245° F., dehydrating the slurry to a brix of about 78.

After the candy is cooked, the cooked candy is sent to the vacuumchamber, where the candy is further dehydrated to a brix of about 80.After leaving the vacuum, the cooked candy is placed in the dosier whereabout 1.5% of strawberry flavoring by weight and about 1% of red cabbagecoloring by weight is added to the cooked candy. To balance theflavoring, about 0.1% citric acid by weight and about 0.1% lactic acidby weight is added to the cooked candy.

After adding the flavoring and coloring, the cooked candy is depositedinto the mogul machine and then cured. After the candies are cured, theyare added to a tumbling drum to break off any starch that is remainingon the candies. As the candies are being tumbled, about 1% fractionatedcoconut oil by weight and about 1% carnauba wax by weight is poured intothe drum to coat the candies to prevent them from sticking together.

Active ingredient (5 mg)   5% Lactic acid   1% Citric Acid   1% Sucrose23.5% Corn Syrup 50.0% Gelatin   7% Sodium bisufate 0.1%-10% Flavoring(natural/artificial)  1.5% Colorant (natural/artificial)  1.0%

Example 15: Taste-Masked Liquid Formulations

An aqueous pharmaceutical composition of the present invention isformulated by preparing a mixture of hydroxyethylcellulose dissolved in50 milliliters of purified water with 0.5 mL of -orange flavoring agent,with potassium phosphate dibasic and potassium phosphate monobasic added(from a hot water mixture). 4.0 mg of active ingredient is then addedand mixed until dissolved. Sodium hydroxide is added to adjust the pH tofrom about 6.7 to about 6.9.

Active ingredient 4.0 mg Hydroxyethylcellulose 10 mg Potassium phosphatedibasic 4.5 mg Potassium phosphate monobasic 4.5 mg Sodium hydroxide 0.1mL Orange flavoring 0.5 mL Purified water 50 mL

Alternative liquid oral formulations are provided below. For each of theformulations below, a sweetener from 0.5% to 2% such as sucralose,mannitol, sucrose and/or a flavoring agent from 0.5% to 2% such asgrape, cherry, bubble gum, orange, lemon, strawberry can be added.Polypropylene glycol can be replaced with one of the PEGs.

Ingredients Concentration LUM001 0.02 to 4 mg/mL Propylene glycol 10 to300 mg/mL Water, q.s. to 1 mL

Ingredients Concentration LUM001 0.02 to 4 mg/mL PEG 200 (or 300, 400,600) 10 to 300 mg/mL Water, q.s. to 1 mL

Ingredients Concentration LUM001 0.02 to 4 mg/mL Propylene glycol 10 to300 mg/mL Sodium lauryl sulfate 1 to 10 mg/mL Water, q.s. to 1 mL

Ingredients Concentration LUM001 0.02 to 4 mg/mL Propylene glycol 10 to300 mg/mL Poloxamer 188 1 to 10 mg/mL Water, q.s. to 1 mL

Example 16: Sachet Formulation

The following formulation is used to produce a sachet for pediatric use.A sweetener from 0.5% to 2% such as sucralose, mannitol, sucrose and/ora flavoring agent from 0.5% to 2% such as grape, cherry, bubble gum,orange, lemon, strawberry can be added. Sugar and sodium lauryl sulfatecan be exchanged with other surfactants.

Ingredients Concentration LUM001 0.05 to 10 mg Soluble Diluent 10 to 500mg Sugar 10 to 250 mg Sodium lauryl sulfate 5 to 50 mg Flavoring agent10 to 100 mg

Example 17: Animal Study

Animal Preparation.

Male Zucker diabetic fatty rats (ZDF/GmiCrl-fa/fa) were purchased fromCharles River (Raleigh, N.C.) and housed under controlled conditions(12:12 light-dark cycle, 24° C. and 50% relative humidity) with freeaccess to rodent food (Purina 5008, Harlan Teklad, Indianapolis, Ind.).All rats arrived at seven weeks of age (±3 days). After a one-weekacclimation period, rats were anesthetized with isoflurane (AbbottLaboratories, IL) and tail-vein blood samples were collected at 9 amwithout fasting. Blood glucose levels were measured using a glucometer(Bayer, Leverkusen, Germany). In order to ensure balanced treatmentgroups, ZDF rats were assigned to six treatment groups based uponbaseline glucose: vehicle (0.5% HPMC, 0.1% Tween80) and five doses of264W94 (0.001, 0.01, 0.1, 1, 10 mg/kg). All treatments were given viaoral gavage twice a day and animals were followed for two weeks withblood samples collected from tail vein at the end of each week at 9 amwithout fasting. Fecal samples were collected for 24 hours during thesecond week of treatment.

Measurement of Clinical Chemistry Parameters.

Non-esterified fatty acids (NEFA), bile acids, and bile acids in fecalextraction were measured using the Olympus AU640 clinical chemistryanalyzer (Beckman Coulter, Irving, Tex.).

Changes in Fecal Bile Acid Excretion and Plasma Bile Acid Concentrations

Oral administration of 264W94 dose-dependently increased bile acids inthe feces. Fecal bile acid concentrations were elevated up to 6.5 foldwith an ED₅₀ of 0.17 mg/kg, when compared to vehicle treated rats. FecalNEFA also slightly increased in 264W94 treated rats. In contrast, plasmabile acid concentrations were decreased dose-dependently in 264W94treated rats. See FIG. 1.

Plasma Bile Acid Levels of ZDF Rats after Administration of AscendingDoses of SC-435 and LUM002.

Male ZDF rats (n=4) were administered vehicle, SC-435 (1, 10 or 30mg/kg) or LUM002 (0.3, 1, 3, 10 or 30 mg/kg) by oral gavage twice a dayfor 2 weeks. Plasma bile acid levels were determined at the end of thesecond week. Plasma bile acid levels were decreased for all doses ofSC-435 and LUM002. Data are expressed as mean values±SEM. See FIG. 2.

Example 18 Animal Study on the Duration of Action and Time to Onset ofASBTI Activity of a Single Oral Dose of LUM001 on Postprandial TotalSerum Bile Acids in Beagle Dogs

Test Compound:

LUM001—Form I

Dosage Preparation and Administration:

LUM001 was dissolved in water at concentrations that required theadministration of 0.2 ml/kg of solution. Solutions were placed intogelatin capsules, Torpac Inc., size 13 Batch 594, East Hanover N.J., andadministered orally.

Dogs:

Male beagle dogs were obtained from Covance Research Products,Cumberland Va. or Marshall Farms USA, Inc., North Rose N.Y. A total of20 dogs, 1 to 5 years old, 6.8 to 15.6 kg body weight, were used inthese experiments. The dogs were conditioned to a 12 hour light/darkcycle and maintained on a feeding restriction of 1 hour per day accessto food (Richman Standard Certified Canine Diet #5007, PMI Nutrition,Inc., St Louis Mo.) from 7 to 8 AM. They were trained to eat a specialmeal promptly within 20 minutes when presented (1 can. 397 g, Evanger's100% Beef for Dogs, Evanger's Dog and Cat Food Co., Inc., Wheeling Ill.,mixed with 50 g of sharp cheddar cheese).

Serum Total Bile Acid (SBA) Measurement:

SBA was measured by an enzymatic assay. SBA values are expressed as g oftotal bile acids/ml of serum.

Control Experiments to Estimate the Rise and Duration of Elevation inSystemic Serum Bile Acid:

Previous work demonstrated that SBA of beagle dogs rises to a peak levelone hour after feeding the meal described above, and remains at aplateau for 4 hours and then declines. To estimate the details of thisplateau, 6 dogs were given a test meal and blood samples for SBAmeasurement were collected at −30, 0, 30, 60, 65, 70, 80, 90, 120, 180,240, 360, 480, 720, 1410 and 1440 minutes from the time of feeding. Anyremaining food was removed 20 min after it was first presented to thedogs. To establish a method for extending the elevated plateau of SBA, 6dogs were given the meal at 0 hr and an additional V2 size meal again 4hr after their first meal. Blood samples were taken at 0, 1, 2, 3, 4,4.5, 6, 7 and 8 hr. The curves for SBA level vs time obtained in theseexperiments were used as references for determining blood sampling timesin experiments with LUM001. Wherever possible, experimental designpermitting, in experiments with test compound, each dog served as itsown simultaneous control, and the mean 1 hr SBA value served as thereference to which all other mean values were compared.

Experiments to Measure Time to Onset of Activity of LUM001:

LUM001 was administered at 0, 0.01, 0.05, 0.2 and 1 mg/kg, p.o. to dogs,n=6, 1 hr after feeding the standard experimental meal. Blood samplesfor SBA measurement were taken at −30, 0, 30, 60, 65, 70, 80, 90, 120and 180 minutes from the time of feeding. Each dog served as its owncontrol, and mean SBA levels were compared to the mean SBA level at 60minutes.

TABLE 1 Onset of Activity of LUM001 on Dog Serum Bile Acid Serum BileAcid (μg/ml) SD-5613 Time Water, n = 6 0.01 mg/kg, n = 6 0.05 mg/kg, n =6 0.2 mg/kg, n = 6 1 mg/kg, n = 6 (min) Mean sem Mean sem Mean sem Meansem Mean sem −30 2.2 0.3 1.5 0.1 1.4 0.1 2.4 0.5 2.1 0.2 0 2.0 0.3 1.40.1 2.1 0.6 1.9 0.2 2.8 0.4 30 6.9 2.1 5.8 2.5 6.8 2.3 9.1 2.1 7.6 1.860 17.8 3.2 14.6 2.8 10.4 1.2 19.1 2.7 13.8 1.4 65 16.6 3.6 13.9 2.412.2 1.7 14.9 1.7 13.5 1.4 70 16.2 1.9 14.1 2.2 12.0 1.6 16.7 2.3 15.41.8 80 16.1 2.3 12.8 1.8 10.0 1.3 14.3 2.2 12.1 1.4 90 15.2 2.8 11.0 2.06.6 1.6 9.8* 0.6 7.4* 1.2 120 15.5 3.6 10.8 1.7 6.5* 1.2 4.8* 0.3 3.0*0.1 180 14.7 3.1 11.0 1.6 6.5* 1.2 4.0 0.6 2.6* 0.2 All animals were fedat 0 minutes and dosed at 60 minutes. *= p < 0.05 compared to 60 minutesvalue in the same curve by two-tailed paired two-sample t-test.

Experiments to Measure the Duration of Action of LUM001:

In dogs a single experimental meal produces a postprandial rise in SBAthat is elevated to a peak at 1 hour after feeding and constant for anadditional 3 hours. Previous experiments (2) indicate that LUM001remains active for more than 4.5 hours. To measure the duration ofaction of an ASBT inhibitor using postprandial SBA levels requires thatin the control situation the SBA levels remain elevated and constant forthe entire period of compound action, or that the compound beadministered long before the postprandial rise occurs, and remain activein the empty digestive system for long periods before feeding.Accordingly, two alternative methods were used to provide a window ofconstant SBA elevation that could be used to measure the duration ofaction of ASBT inhibitors.

Method 1: Two Meals for Extended SBA Elevation:

LUM001 was administered at 0.05 and 0.2 mg/kg, p.o. to 6 dogs 1 hr afterfeeding them a meal. At 4 hours after the meal was offered, a secondmeal of ½ the size of the first meal was offered. It too was consumed aspromptly and thoroughly as the first meal, and provided an extended,constant SBA plateau. Blood samples for SBA measurement were taken at 0,1, 1.5, 2, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5 and 8 hours from the time ofoffering the first meal. Mean SBA levels were compared to the mean SBAlevel at 1 hour, each dog serving as its own control. The end ofactivity is considered to occur at time point at which the mean SBAvalue is not significantly lower than the 1 hr mean value.

TABLE 2 Duration of Action of LUM001 on Dog Serum Bile Acids I SerumBile Acid (μg/ml) SD-5613 Water, n = 6 0.05 mg/kg, n = 6 0.2 mg/kg, n =6 Time (hr) Mean SEM Mean SEM Mean SEM 0 2.5 0.5 1.4 0.1 1.3 0.1 1 13.11.3 9.2 1.8 11.1 1.5 1.5 9.6 2.0 9.1 0.6 2 14.6 1.2 6.7 0.6 3.8* 0.4 814.4 1.7 4 14.8 1.2 5.1* 0.7 2.5* 0.4 4.5 16.6 1.5 6.4 0.7 3.3* 0.6 515.8 2.0 7.0 0.7 3.1* 0.4 6 15.5 2.1 7.0 0.9 3.6* 0.7 7 14.4 2.5 7.4 0.83.9* 0.5 8 13.3 1.5 6.5 1.1 5.8* 0.8 All animals were fed a full meal at0 hour, dosed orally with the compound at 1 hour and then fed anadditional one-half meal at 4 hours. *= p < 0.05 compared to the meanvalue in the same curve at 1 hour by two-tailed paired two-samplet-test.

Method 2: One Meal and Extended Interval Between Dosing and Feeding:

Alternatively, 6 dogs were dosed with water or LUM001, at 0.05 mg/kg,p.o. at 1.5 hours prior to being fed, or 0.05, or 0.2 mg/kg, at 2 hoursprior to feeding. This moved the elevated SBA plateau out in time fromthe dose point. Blood samples for SBA measurement were taken immediatelybefore dosing (0 or 0.5 hr), at feeding (2 hr), 2.5, 3, 4 and 5 hoursafter feeding. This allowed detection of activity out to 5.5 and 6 hoursafter dosing without feeding the dogs a second time. Mean SBA levelswere compared to the corresponding mean SBA levels in water treatedcontrols. The end of activity is considered to occur at the first timepoint at which the mean SBA value is not significantly lower than thecorresponding control mean value.

TABLE 3 Duration of Action of LUM001 on Dog Serum Bile Acids II SerumBile Acid (μg/ml) Dosing Time 0.5 hr 0 hr 0 hr Feeding time 2 hr 2 hr 2hr 2 hr Water, 0.05 mg/kg, 0.05 mg/kg, 0.2 mg/kg, SD-5613 n = 6 n = 9 n= 9 n = 6 Time (hr) Mean SEM Mean SEM Mean SEM Mean SEM 0 1.7 0.1 1.30.1 0.5 1.8 0.3 2 2.0 0.3 1.7 0.1 2.0 0.5 1.7 0.3 2.5 6.9 2.1 2.5 0.6 317.8 3.2 9.7 2.6 9.0* 1.4 4.1* 0.6 4 15.5 3.6 12.4 2.0 10.8 1.2 6.5* 0.85 14.7 3.1 11.6 2.4 10.6 0.9 7.9* 1.1 *= p < 0.05 vs water treatmeat bytwo-tailed two-sample t-test without assuming equal variances.

Conclusion:

In the dog SBA model, the ED₅₀ dose (0.2 mg/kg) of LUM001 administeredorally 1 hour after feeding significantly lowered serum bile acid levelswithin 30 minutes of dosing and these levels remained significantlylowered for at least 6 hours. By comparison, a threshold dose of 0.05mg/kg significantly lowered SBA levels within approximately 1 to 2 hoursafter dosing but the significant decrease was not sustained beyond 3hours after dosing. Increasing the dose above the ED₅₀ level to 1 mg/kgdid not shorten the onset time to significant SBA lowering and stillsustained a maximal suppression for 2 hours after dosing. When LUM001was administered 2 hours prior to feeding, a dose of 0.2 mg/kg wasrequired produce a significant effect that was sustained for at least2-3 hours after feeding. The results from these studies indicate thatthe presence of food in the GI tract has a significant impact on thepharmacodynamic activity of the ASBT inhibitor, most likely by alteringthe residence time of the drug in the small intestine.

Example 19 A Randomized Double-Blind, Placebo Controlled, Safety,Tolerability, Pharmacokinetic, and Pharmacodynamic Study of AscendingMultiple Oral Doses of LUM001 in Healthy Subjects

This Phase 1 study was a randomized, double-blind, placebo-controlledstudy of ascending multiple oral doses of LUM001 in healthy, adultsubjects. This study was conducted at a single center. There were 13LUM001 dosing panels: 10, 20, 60, 100, and 20 mg every morning (qAM) (2)(i.e., the regimen was tested a second time in the study), 5 mg everyevening (qPM), 0.5, 1, 2.5, 5, 2.5 (2), 5 (2), and 0.5 to 5 mg qAM dosetitration. Most of the dosing panels included subjects treated withmatching placebo. Shown in the graphs are data from the 0.5 (n=16), 1.0(n=8), 2.5 (n=8), 5.0 (n=8) and 10 (n=8) mg dosing groups.

For the qAM dosing panels, LUM001 or placebo was administered each dayof the treatment period (28 days) immediately prior to the morning mealat approximately 08:00 and after any necessary blood work was drawn.

Serum Bile Acid (SBA) Analysis:

On Day −1, blood was drawn for baseline SBA at approximately 30 minutesbefore and after breakfast and 30 minutes after lunch and dinner. Duringthe treatment period, samples were obtained on days 2, 14 and 28 (14 dayresults are presented in FIG. 3) at −30, 30, 60 120, and 240 minutesafter each of the 3 daily meals for analysis. For each sample,approximately 3 mL of venous blood were collected by venipuncture orsaline lock.

SBA were analyzed as part of the routine clinical analysis of the serumsamples collected at each time point.

Fecal Bile Acid Analysis:

Fecal samples were collected for all panels except the dose-titrationpanel, 2.5 (2) and 5 mg (2), on Days 9 through 14 and 23 through 28(data shown in FIG. 4). Twenty-four hour FBA excretions were quantifiedby Pharmacia for Days 9 through 14 and 23 through 28. Feces werecollected in a 24-hour collection container beginning at 08:00 andending 24 hours later. This procedure was followed on Days 9 through 14and 23 through 28, with new collection containers issued for each24-hour period. The weight of each 24-hour fecal collection was recordedon the CRFs. Specimens were stored in 24-hour containers, frozen atapproximately −80° C. prior to analysis.

An aliquot for each 24-hour fecal sample collected on Days 23 through 28was combined, homogenized, and analyzed for bile acid speciesconcentrations by ANAPHARM. The fecal bile acid species evaluatedinclude chenodeoxycholic acid, cholic acid, deoxycholic acid, andlithocholic acid.

Conclusion:

The results showed a significant reduction in serum bile acids andsignificant increase in fecal bile acids.

Example 20 Pediatric Study to Test Efficacy of ASBTI in Lowering SerumBile Acids in Pediatric Patients

LUM001 has been administered to forty patients under the age of 18 yearsold. Table below shows the exemplary characteristics of five childrenwho received LUM001. The drug was administered once-a-day (QD) in themorning for fourteen days. The levels of systemic exposure of LUM001were measured on day eight and the drug was confirmed to be minimallyabsorbed by the children. These doses are similar to those using totreat children with cholestatic diseases.

TABLE 4 Pharmacokinetics of LUM001 in pediatric subjects (studyNB-00-02-014) LUM001 Average Subject treatment Dose serum drug Number(mg) Sex μg/kg exposure (ng/ml) 0309 1.0 MALE 35.0 0.0 0304 1.0 MALE24.3 0.0 0308 1.0 MALE 28.9 0.0 0410 2.5 FEMALE 42.0 0.0 0510 5.0 MALE168.4 0.0

The efficacy of LUM001 was determined by measuring total serum bileacids after eight days of dosing in children and adolescents under theage of eighteen. Thirty minutes before the next drug administration, atapproximately 8 am in the morning, serum bile acid levels were measured.The child had refrained from food for 12 hours prior to this sample thusproviding a fasted level of serum bile acid. After breakfast, serum bileacids were measured for up to the next 4 hours (8 am to noon) and thepeak serum bile acid concentration noted. LUM001 was shown to generallydecrease both the fasting and post-prandial peak levels of serum bileacids (see table). In the table below the placebo patients had anaverage fasting serum bile acid level of 8.6 μmol/L and a post-prandialpeak serum bile acid level of 11.9 μmol/L. For the LUM001 treatedpatients the values were 6.5 μmol/L and 9.2, respectively, representinga 24% and 23% decrease (see FIG. 5).

TABLE 5 Fasting SBA and morning post-prandial peak in pediatric subjectsPatients 301 307 405 408 508 304 308 309 401 510 Drug dose (mg) PlaceboPlacebo Placebo Placebo Placebo 1 1 1 2.5 5 Fasting serum bile 9.1 7.410.5 8.3 7.7 5.6 6.8 6.9 6.0 7.4 acid (μmol/l) Morning Post- 11.9 10.713.1 13.4 10.4 8.4 9.3 10.0 6.8 11.3 prandial peak (μmol/l)

Example 21

Clinical Trial to Test Efficacy of ASBTI in Treatment and/or Alleviationof Symptoms of Pediatric Cholestasis or a Pediatric Cholestatic LiverDisease

This study will determine efficacy of ASBTI treatment in patientsafflicted with pediatric cholestasis or a pediatric cholestatic liverdisease.

Subjects under the age of 12, clinically diagnosed with cholestasis or acholestatic liver disease will be enrolled. Subjects may be diagnosed bysymptoms such as jaundice, chronic pruritis, total serum bileacid/bilirubin elevation.

Subjects who have life threatening renal disease, cardiovasculardisease, or congenital anomalities will be excluded.

Subjects will be administered a daily oral dose of compound LUM001formulated for release in the distal ileum. Alternatively, any of thefollowing compounds can be the subject of the clinical trial: 264W94;SAR548304B; SA HMR1741;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine.

The primary endpoint is the proportion of subjects showing resolution orimprovement of baseline signs and symptoms, e.g., jaundice, serum levelsof bile acids/salts and/or bilirubin, pruritis.

Example 22

Clinical Trial to Test Efficacy of ASBTI in Treatment and/or Alleviationof Symptoms of Progressive Familial Intrahepatic Cholestasis 1 (PFIC-1)

This study will determine efficacy of an ASBTI for treatment inpediatric patients afflicted with PFIC1.

Patients genetically diagnosed with anomalies in ATP8B 1, ABCB11, orABCB4 gene and who present with PFIC-1 are eligible for enrollment.

Inclusion criteria include severe pruritus (greater than grade II);non-responsive to ursodiol; native liver; genetic or immunohistochemicalfindings consistent with PFIC1 or Alagille syndrome; informed consent;age 12 months or older.

Exclusion criteria include chronic diarrhea requiring IV fluid ornutritional interventions; surgical interruption of the enterohepaticcirculation; or decompensated cirrhosis (PT >16s, alb <3.0 gr/dl,ascites, diuretic therapy, variceal hemorrhage, encephalopathy).

Subjects will be administered a daily oral dose of LUM001 formulated forrelease in the distal ileum. Alternatively, any of the followingcompounds can be the subject of the clinical trial: 264W94; SAR548304B;SA HMR1741;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine.

Stage 1 will be a 4 week dose escalation study to determine patientminimum tolerated dose. Dose 1: 14 ug/kg/day for 7 days; dose 2: 35ug/kg/day for 7 days; dose 3; 70 ug/kg/day for 7 days; dose 4: 140ug/kg/day for 7 days.

Stage 2 will be a double-blind placebo controlled cross-over study.Subjects will be randomized to maximum tolerated dose or placebo for 8weeks, followed by a 2 week drug holiday, and cross-over to receive thealternative regimen for 8 week.

The primary endpoint is the proportion of subjects showing resolution orimprovement of baseline signs and symptoms, e.g., jaundice, serum levelsof bile acids/salts and/or bilirubin, pruritis.

Example 23

Clinical Trial to Test Efficacy of ASBTI in Treatment and/or Alleviationof Symptoms of Benign Recurrent Intrahepatic Cholestasis or aCholestatic Liver Disease (BRIC)

The purpose of this study is to determine the effect of a non-systemicASBTI suspension in treating BRIC. An enteric ileal pH-releasesuspension of an ASBTI may also be administered to a subject once a day.

Pediatric patients genetically diagnosed with anomalies in ATP8B 1,ABCB11, or ABCB4 gene and present non-chronic but recurrent cholestasisor a cholestatic liver disease symptoms will be enrolled.

Subjects will be administered a daily oral dose of compound LUM001formulated for release in the distal ileum. Alternatively, any of thefollowing compounds can be the subject of the clinical trial: 264W94;SD5613; SAR548304B; SA HMR1741;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine.The primary endpoint is the proportion of subjects showing resolution orimprovement of baseline signs and symptoms, e.g., jaundice, serum levelsof bile acids/salts and/or bilirubin, pruritis.

Example 24

Clinical Trial to Test Efficacy of ASBTI in Treatment and/or Alleviationof Symptoms of Total Parenteral Nutrition Associated Cholestasis or aCholestatic Liver Disease (TPN-AC)

The purpose of this study is to determine the effect of a non-systemicASBTI suspension in treating TPN-AC. An enteric ileal pH-releasesuspension of an ASBTI may also be administered to a subject once a day.

Pediatric patients clinically diagnosed with TPN-AC and associatedsymptoms will be enrolled.

Subjects will be administered a daily oral dose of compound LUM001formulated for release in the distal ileum. Alternatively, any of thefollowing compounds can be the subject of the clinical trial: 264W94;SAR548304B; SA HMR1741;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—[(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl]carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine.The primary endpoint is the proportion of subjects showing resolution orimprovement of baseline signs and symptoms, e.g., jaundice, serum levelsof bile acids/salts and/or bilirubin, pruritis.

Example 25

Clinical Trial to Test Efficacy of LUM-001 in Treatment and/orAlleviation of Symptoms of FIC1 Disease and Alagille Syndrome

Pediatric patients who suffer from FIC1 disease (n=15) and Alagillesyndrome (n=20) aged 12 months and older will be tested.

Inclusion criteria will include (1) severe pruritus (>grade II)unresponsive to routine pharmacologic therapy, (2) native liver, (3)genetic or clinical findings consistent with FIC1 disease or geneticfindings of Alagille syndrome, and (4) informed consent and assent asappropriate.

Exclusion criteria will include (1) chronic diarrhea requiring specificintravenous fluid or nutritional intervention for the diarrhea and/orits sequalae or (2) surgical interruption of the enterohepaticcirculation, (3) decompensated cirrhosis (PT >16s, alb <3.0 gr/dl,ascites, diuretic therapy, variceal hemorrhage, encephalopathy).

Stage 1: 4 week dose escalation of LUM-001 (doses based onadolescent/adult doses) to determine patient maximum tolerated dose.Dose 1-14 μg/kg/day for seven days; Dose 2-35 μg/kg/day for seven days;Dose 3-70 μg/kg/day for seven days; Dose 4-140 μg/kg/day for seven days.

Stage 2: double-blinded placebo controlled cross-over study. Randomizedto maximum tolerated dose or placebo for 8 weeks, followed by 2 weekswash out, and crossed-over to receive the alternative regimen for 8weeks.

Possible Stage 3 with open label therapy.

Primary endpoint: safety and tolerability of LUM-001.

Secondary endpoints: changes in pruritus scores, clinical laboratories,fecal bile acid secretion, serum bile acids and serum7α-hydroxy-4-cholesten-3-one (7αC4).

Baseline assessment will include: FIC1 or Jagged 1 genotyping, completehistory and physical, comprehensive clinical laboratory profile, 72 hourfecal bile acid collection, serum levels of bile acids, bile acidsynthesis marker (7αC4).

Stage 1-Baseline assessments (except genotyping, history and physical)will be repeated at the end of each 7-day treatment period. Pruritusscoring will be assessed by the parents, child (if possible) and byclinician(s) at the beginning and end of each dose.

Stage 2-Baseline assessments (except genotyping, history and physical)will be repeated at the end of each 8 week treatment period.

LUM-001 was shown to be well-tolerated in a pediatric multiple-dosestudy: 2 weeks daily up to 5 mg q.d. (39 treated subjects aged 10-17).

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A method for treating or ameliorating a pediatriccholestatic liver disease comprising non-systemically administering to apediatric patient a therapeutically effective amount of a pharmaceuticalcomposition comprising an Apical Sodium-dependent Bile Acid TransporterInhibitor (ASBTI) or a pharmaceutically acceptable salt thereof.
 2. Amethod for treating or ameliorating pruritis comprising non-systemicallyadministering to a pediatric patient suffering from a pediatriccholestatic liver disease a therapeutically effective amount of apharmaceutical composition comprising an Apical Sodium-dependent BileAcid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable saltthereof.
 3. A method for treating or ameliorating pediatrichypercholemia comprising non-systemically administering to a pediatricpatient a therapeutically effective amount of a pharmaceuticalcomposition comprising an Apical Sodium-dependent Bile Acid TransporterInhibitor (ASBTI) or a pharmaceutically acceptable salt thereof.
 4. Amethod for decreasing the level of serum bile acids or hepatic bileacids in a pediatric patient suffering from a pediatric cholestaticliver disease comprising non-systemically administering to the patient atherapeutically effective amount of a pharmaceutical compositioncomprising Apical Sodium-dependent Bile Acid Transporter Inhibitor(ASBTI) or a pharmaceutically acceptable salt thereof.
 5. The method ofclaim 4, wherein the method comprises decreasing at least 20% of serumbile acid or hepatic bile acid levels in the patient.
 6. The method ofclaim 1, wherein the method comprises reducing xanthoma, serumlipoprotein X, liver enzymes, bilirubin, intraenterocyte bileacids/salts, or necrosis and/or damage to hepatocellular architecture.7. The method of claim 1, wherein the composition is a pediatric dosageform.
 8. The method of claim 7, wherein the pediatric dosage form isselected from a solution, syrup, suspension, elixir, powder forreconstitution as suspension or solution, dispersible/effervescenttablet, chewable tablet, gummy candy, lollipop, freezer pops, troches,oral thin strips, orally disintegrating tablet, sachet, soft gelatincapsule, and sprinkle oral powder or granules.
 9. The method of claim 1,wherein the dosage of the ASBTI is between about 10 μg/kg/day and about300 μg/kg/day.
 10. The method of claim 1, wherein the dosage of theASBTI is any dosage from about 14 μg/kg/day to about 280 μg/kg/day. 11.The method of claim 1, wherein the dosage of the ASBTI is any dosagefrom about 14 μg/kg/day to about 140 μg/kg/day.
 12. The method of claim1, wherein the dosage comprises between 0.1 to 20 mg of the ASBTI. 13.The method of claim 1, wherein the pediatric cholestatic liver diseaseis progressive familial intrahepatic cholestasis (PFIC), PFIC type 1,PFIC type 2, PFIC type 3, Alagille syndrome, Dubin-Johnson Syndrome,biliary atresia, post-Kasai biliary atresia, post-liver transplantationbiliary atresia, post-liver transplantation cholestasis, post-livertransplantation associated liver disease, intestinal failure associatedliver disease, bile acid mediated liver injury, pediatric primarysclerosing cholangitis, MRP2 deficiency syndrome, neonatal sclerosingcholangitis, a pediatric obstructive cholestasis, a pediatricnon-obstructive cholestasis, a pediatric extrahepatic cholestasis, apediatric intrahepatic cholestasis, a pediatric primary intrahepaticcholestasis, a pediatric secondary intrahepatic cholestasis, benignrecurrent intrahepatic cholestasis (BRIC), BRIC type 1, BRIC type 2,BRIC type 3, total parenteral nutrition associated cholestasis,paraneoplastic cholestasis, Stauffer syndrome, drug-associatedcholestasis, infection-associated cholestasis, or gallstone disease. 14.The method of claim 1, wherein the pediatric cholestatic liver diseaseis characterized by one or more symptoms selected from jaundice,pruritis, cirrhosis, hypercholemia, neonatal respiratory distresssyndrome, lung pneumonia, increased serum concentration of bile acids,increased hepatic concentration of bile acids, increased serumconcentration of bilirubin, hepatocellular injury, liver scarring, liverfailure, hepatomegaly, xanthomas, malabsorption, splenomegaly, diarrhea,pancreatitis, hepatocellular necrosis, giant cell formation,hepatocellular carcinoma, gastrointestinal bleeding, portalhypertension, hearing loss, fatigue, loss of appetite, anorexia,peculiar smell, dark urine, light stools, steatorrhea, failure tothrive, and renal failure.
 15. The method of claim 1, wherein thepediatric patient is between 6 months to 12 years old.
 16. The method ofclaim 1, wherein less than 10% of the ASBTI is systemically absorbed.17. The method of claim 1, wherein the ASBTI is a compound of FormulaII:

wherein: q is an integer from 1 to 4; n is an integer from 0 to 2; R¹and R² are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl, wherein alkyl,alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl,dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹⁰R^(w)A⁻, SR⁹, S⁺R⁹R¹⁰A⁻, P⁺R⁹R¹⁰R¹¹A⁻,S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰, whereinalkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl,(polyalkyl)aryl, and cycloalkyl optionally have one or more carbonsreplaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, P⁺R⁹R¹⁰A⁻, orphenylene, wherein R⁹, R¹⁰, and R^(w) are independently selected fromthe group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl,acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; orR¹ and R² taken together with the carbon to which they are attached formC₃-C₁₀ cycloalkyl; R³ and R⁴ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle,OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, and SO₃R⁹, wherein R⁹ and R¹⁰ are asdefined above; or R³ and R⁴ together ═O, ═NOR¹¹, ═S, ═NNR¹¹R¹², ═NR⁹, or═CR¹¹R¹², wherein R¹¹ and R¹² are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl,alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl,cyanoalkyl, OR⁹, NR⁹R¹⁰, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen,oxo, and CONR⁹R¹⁰, wherein R⁹ and R¹⁰ are as defined above, providedthat both R³ and R⁴ cannot be OH, NH₂, and SH, or R¹¹ and R¹² togetherwith the nitrogen or carbon atom to which they are attached form acyclic ring; R⁵ and R⁶ are independently selected from the groupconsisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle,quaternary heterocycle, quaternary heteroaryl, OR⁹, SR⁹, S(O)R⁹, SO₂R⁹,SO₃R⁹, and -L_(z)-K_(z); wherein z is 1, 2 or 3; each L is independentlya substituted or unsubstituted alkyl, a substituted or unsubstitutedheteroalkyl, a substituted or unsubstituted alkoxy, a substituted orunsubstituted aminoalkyl group, a substituted or unsubstituted aryl, asubstituted or unsubstituted heteroaryl, a substituted or unsubstitutedcycloalkyl, or a substituted or unsubstituted heterocycloalkyl; each Kis a moiety that prevents systemic absorption; wherein alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, andquaternary heteroaryl can be substituted with one or more substituentgroups independently selected from the group consisting of alkyl,alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl,halogen, oxo, R¹⁵, OR¹³, OR¹³R¹⁴, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³,SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,C(O)NR¹³R¹⁴, C(O)OM, CR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴,S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, wherein: A⁻ is a pharmaceuticallyacceptable anion and M is a pharmaceutically acceptable cation, saidalkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, and heterocycle can be further substituted with one or moresubstituent groups selected from the group consisting of OR⁷, NR⁷R⁸,S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A⁻, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternaryheterocycle, quaternary heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸ and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one ormore carbons replaced by O, NR⁷, N⁺R⁷R⁸A⁻, S, SO, SO₂, S⁺R⁷A⁻, PR⁷,P(O)R⁷, P⁺R⁷R⁸A⁻, or phenylene, and R¹³, R¹⁴, and R¹⁵ are independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl,quaternary heterocycle, quaternary heteroaryl, quaternaryheteroarylalkyl, and -G-T-V-W, wherein alkyl, alkenyl, alkynyl,arylalkyl, heterocycle, and polyalkyl optionally have one or morecarbons replaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, PR,P⁺R⁹R¹⁰A⁻, P(O)R⁹, phenylene, carbohydrate, C₂-C₇ polyol, amino acid,peptide, or polypeptide, and G, T and V are each independently a bond,—O—, —S—, —N(H)—, substituted or unsubstituted alkyl, —O-alkyl,—N(H)-alkyl, —C(O)N(H)—, —N(H)C(O)—, —N(H)C(O)N(H)—, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted heterocycle,substituted or unsubstituted carboxyalkyl, substituted or unsubstitutedcarboalkoxyalkyl, or substituted or unsubstituted cycloalkyl, and W isquaternary heterocycle, quaternary heteroaryl, quaternaryheteroarylalkyl, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹⁰R¹¹A⁻, OS(O)₂OM, or S⁺R⁹R¹⁰A⁻, andR¹³, R¹⁴ and R¹⁵ are optionally substituted with one or more groupsselected from the group consisting of sulfoalkyl, quaternaryheterocycle, quaternary heteroaryl, OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰,PO(OR¹⁶)OR¹⁷, P⁺R⁹R¹⁰R¹¹A⁻, S⁺R⁹R¹⁰A⁻, and C(O)OM, wherein R¹⁶ and R¹⁷are independently selected from the substituents constituting R⁹ and M;or R¹⁴ and R¹⁵, together with the nitrogen atom to which they areattached, form a cyclic ring; and is selected from the group consistingof alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle,ammoniumalkyl, alkylammoniumalkyl, and arylalkyl; and R⁷ and R⁸ areindependently selected from the group consisting of hydrogen and alkyl;and one or more R are independently selected from the group consistingof H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl,halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether,quaternary heterocycle, quaternary heteroaryl, OR¹³, NR¹³R¹⁴, SR¹³,S(O)R¹³, S(O)₂R¹³, SO₃R¹³, S⁺R¹³R¹⁴A⁻, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, NR¹⁴C(O)R¹³, C(O)NR¹³R¹⁴,NR¹⁴C(O)R¹³, C(O)OM, COR¹³, OR¹⁸, S(O)_(n) NR¹⁸, NR¹³R¹⁸, NR¹⁸R¹⁴,N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹¹R¹²A⁻, amino acid, peptide, polypeptide, andcarbohydrate; wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl,polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether,quaternary heterocycle, and quaternary heteroaryl can be furthersubstituted with OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹,oxo, CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷,P⁺R⁹R¹¹R¹²A⁻, S⁺R⁹R¹⁰A⁻, or C(O)M, wherein W is O or NH, R³¹ is selectedfrom wherein R¹⁸ is selected from the group consisting of acyl,arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, whereinacyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,quaternary heterocycle, and quaternary heteroaryl optionally aresubstituted with one or more substituents selected from the groupconsisting of OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, oxo,CO₃R⁹, CN, halogen, CONR⁹R¹⁰, SO₃R⁹, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷, andC(O)OM, wherein in R^(x), one or more carbons are optionally replaced byO, NR¹³, N⁺R¹³R¹⁴A⁻, SO, SO₂, S⁺R¹³A⁻, PR¹³, P(O)R³, P⁺R¹³R¹⁴A⁻,phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, orpolyalkyl, wherein in said polyalkyl, phenylene, amino acid, peptide,polypeptide, and carbohydrate, one or more carbons are optionallyreplaced by O, NR⁹, R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, PR⁹, P⁺R⁹R¹⁰A⁻, orP(O)R⁹; wherein quaternary heterocycle and quaternary heteroaryl areoptionally substituted with one or more groups selected from the groupconsisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl,haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR¹³,NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³, SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂,CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴, C(O)NR¹³R¹⁴, C(O)OM, COR¹³,P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴, S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻,provided that both R⁵ and R⁶ cannot be hydrogen or SH; provided thatwhen R⁵ or R⁶ is phenyl, only one of R¹ or R² is H; provided that whenq=1 and R^(x) is styryl, anilido, or anilinocarbonyl, only one of R⁵ orR⁶ is alkyl; or a pharmaceutically acceptable salt, solvate, or prodrugthereof.
 18. The method of claim 17, wherein: q is 1; n is 2; R isN(CH₃)₂; R⁷ and R⁸ are independently H; R¹ and R² is alkyl; R³ is H, andR⁴ is OH; R⁵ is H, and R⁶ is selected from the group consisting ofalkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternaryheterocycle, quaternary heteroaryl, OR⁹, SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, and-L_(z)-K_(z); wherein z is 1, 2 or 3; each L is independently asubstituted or unsubstituted alkyl, a substituted or unsubstitutedheteroalkyl, a substituted or unsubstituted alkoxy, a substituted orunsubstituted aminoalkyl group, a substituted or unsubstituted aryl, asubstituted or unsubstituted heteroaryl, a substituted or unsubstitutedcycloalkyl, or a substituted or unsubstituted heterocycloalkyl; each Kis a moiety that prevents systemic absorption; wherein alkyl, alkenyl,alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, andquaternary heteroaryl can be substituted with one or more substituentgroups independently selected from the group consisting of alkyl,alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl,heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl,halogen, oxo, R¹⁵, OR¹³, OR¹³R¹⁴, NR¹³R¹⁴, SR¹³, S(O)R¹³, SO₂R¹³,SO₃R¹³, NR¹³OR¹⁴, NR¹³NR¹⁴R¹⁵, NO₂, CO₂R¹³, CN, OM, SO₂OM, SO₂NR¹³R¹⁴,C(O)NR¹³R¹⁴, C(O)OM, CR¹³, P(O)R¹³R¹⁴, P⁺R¹³R¹⁴R¹⁵A⁻, P(OR¹³)OR¹⁴,S⁺R¹³R¹⁴A⁻, and N⁺R⁹R¹¹R¹²A⁻, wherein A⁻ is a pharmaceuticallyacceptable anion and M is a pharmaceutically acceptable cation, saidalkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl,cycloalkyl, and heterocycle can be further substituted with one or moresubstituent groups selected from the group consisting of OR⁷, NR⁷R⁸,S(O)R⁷, SO₂R⁷, SO₃R⁷, CO₂R⁷, CN, oxo, CONR⁷R⁸, N⁺R⁷R⁸R⁹A⁻, alkyl,alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternaryheterocycle, quaternary heteroaryl, P(O)R⁷R⁸, P⁺R⁷R⁸R⁹A⁻, and P(O)(OR⁷)OR⁸ and wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether,aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one ormore carbons replaced by O, NR⁷, N⁺R⁷R⁸A⁻, S, SO, SO₂, S⁺R⁷A⁻, PR⁷,P(O)R⁷, P⁺R⁷R⁸A⁻, or phenylene, and R¹³, R¹⁴, and R¹⁵ are independentlyselected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl,quaternary heterocycle, quaternary heteroaryl, quaternaryheteroarylalkyl, and -G-T-V-W, wherein alkyl, alkenyl, alkynyl,arylalkyl, heterocycle, and polyalkyl optionally have one or morecarbons replaced by O, NR⁹, N⁺R⁹R¹⁰A⁻, S, SO, SO₂, S⁺R⁹A⁻, PR,P⁺R⁹R¹⁰A⁻, P(O)R⁹, phenylene, carbohydrate, C₂-C₇ polyol, amino acid,peptide, or polypeptide, and G, T and V are each independently a bond,—O—, —S—, —N(H)—, substituted or unsubstituted alkyl, —O-alkyl,—N(H)-alkyl, —C(O)N(H)—, —N(H)C(O)—, —N(H)C(O)N(H)—, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted arylalkyl,substituted or unsubstituted alkenylalkyl, alkynylalkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted heterocycle,substituted or unsubstituted carboxyalkyl, substituted or unsubstitutedcarboalkoxyalkyl, or substituted or unsubstituted cycloalkyl, and W isquaternary heterocycle, quaternary heteroaryl, quaternaryheteroarylalkyl, N⁺R⁹R¹¹R¹²A⁻, P⁺R⁹R¹⁰R¹¹A⁻, OS(O)₂OM, or S⁺R⁹R¹⁰A⁻, andR⁹ and R¹⁰ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle,ammoniumalkyl, arylalkyl, and alkylammoniumalkyl; R¹¹ and R¹² areindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle,carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR⁹, NR⁹R¹⁰,SR⁹, S(O)R⁹, SO₂R⁹, SO₃R⁹, CO₂R⁹, CN, halogen, oxo, and CONR⁹R¹⁰,wherein R⁹ and R¹⁰ are as defined above, provided that both R³ and R⁴cannot be OH, NH₂, and SH, or R¹¹ and R¹² together with the nitrogen orcarbon atom to which they are attached form a cyclic ring; R¹³, R¹⁴ andR¹⁵ are optionally substituted with one or more groups selected from thegroup consisting of sulfoalkyl, quaternary heterocycle, quaternaryheteroaryl, OR⁹, NR⁹R¹⁰, N⁺R⁹R¹¹R¹²A⁻, SR⁹, S(O) R⁹, SO₂R⁹, SO₃R⁹, oxo,CO₂R⁹, CN, halogen, CONR⁹R¹⁰, SO₂OM, SO₂NR⁹R¹⁰, PO(OR¹⁶)OR¹⁷,P⁺R⁹R¹⁰R¹¹A⁻, S⁺R⁹R¹⁰A⁻, and C(O)OM, wherein R¹⁶ and R¹⁷ areindependently selected from the substituents constituting R⁹ and M; orR¹⁴ and R¹⁵, together with the nitrogen atom to which they are attached,form a cyclic ring; and is selected from the group consisting of alkyl,alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl,alkylammoniumalkyl, and arylalkyl; or a pharmaceutically acceptablesalt, solvate, or prodrug thereof.
 19. The method of claim 17, whereinthe compound of Formula II is


20. The method of claim 17, wherein the compound of Formula II is


21. The method of claim 17, wherein the compound of Formula II is


22. The method of claim 1, wherein the ASBTI is a compound of Formula I:

wherein: R¹ is a straight chained C₁₋₆ alkyl group; R² is a straightchained C₁₋₆ alkyl group; R³ is hydrogen or a group OR¹¹ in which R¹¹ ishydrogen, optionally substituted C₁₋₆ alkyl or a C₁₋₆ alkylcarbonylgroup; R⁴ is pyridyl or optionally substituted phenyl or -L_(z)-K_(z);wherein z is 1, 2 or 3; each L is independently a substituted orunsubstituted alkyl, a substituted or unsubstituted heteroalkyl, asubstituted or unsubstituted alkoxy, a substituted or unsubstitutedaminoalkyl group, a substituted or unsubstituted aryl, a substituted orunsubstituted heteroaryl, a substituted or unsubstituted cycloalkyl, ora substituted or unsubstituted heterocycloalkyl; each K is a moiety thatprevents systemic absorption; R⁵, R⁶, R⁷ and R⁸ are the same ordifferent and each is selected from hydrogen, halogen, cyano,R⁵-acetylide, OR¹⁵, optionally substituted C₁₋₆ alkyl, COR¹⁵, CH(OH)R¹⁵,S(O)_(n)R¹⁵, P(O)(OR¹⁵)₂, OCOR¹⁵, OCF3, OCN, SCN, NHCN, CH₂OR¹⁵, CHO,(CH₂)_(p)CN, CONR¹²R¹³, (CH₂)_(p)CO₂R¹⁵, (CH₂)_(p)NR¹²R¹³, CO₂R¹⁵,NHCOCF₃, NHSO₂R¹⁵, OCH₂OR¹⁵, OCH═CHR¹⁵, O(CH₂CH₂O)_(n)R¹⁵,O(CH₂)_(p)SO₃R¹⁵, O(CH₂)_(p)NR¹²R¹³, O(CH₂)_(p)N⁺R¹²R¹³R¹⁴ and —W—R³¹,wherein W is O or NH, and R³¹ is selected from

wherein p is an integer from 1-4, n is an integer from 0-3 and, R¹²,R¹³, R¹⁴ and R¹⁵ are independently selected from hydrogen and optionallysubstituted C₁₋₆ alkyl; or R⁶ and R⁷ are linked to form a group

wherein R¹² and R¹³ are as hereinbefore defined and m is 1 or 2; and R⁹and R¹⁰ are the same or different and each is selected from hydrogen orC₁₋₆ alkyl; and salts, solvates and physiologically functionalderivatives thereof.
 23. The method of claim 22, wherein the compound ofFormula I is


24. The method of claim 1, wherein the ASBTI is a compound of FormulaIII:

wherein: each R¹, R² is independently H, hydroxy, alkyl, alkoxy,—C(═X)YR⁸, —YC(═X)R⁸, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted aryl,substituted or unsubstituted alkyl-aryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted alkyl-cycloalkyl, substitutedor unsubstituted heteroaryl, substituted or unsubstitutedalkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted alkyl-heterocycloalkyl, or -L-K; or R¹ andR² together with the nitrogen to which they are attached form a3-8-membered ring that is optionally substituted with R⁸; each R³, R⁴ isindependently H, hydroxy, alkyl, alkoxy, —C(═X)YR⁸, —YC(═X)R⁸,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkyl-cycloalkyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted alkyl-heterocycloalkyl, or -L-K; R⁵ is H, hydroxy, alkyl,alkoxy, —C(═X)YR⁸, —YC(═X)R⁸, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted alkyl-aryl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted alkyl-heterocycloalkyl, each R⁶, R⁷ isindependently H, hydroxy, alkyl, alkoxy, —C(═X)YR⁸, —YC(═X)R⁸,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted alkyl-aryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkyl-cycloalkyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted alkyl-heteroaryl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted alkyl-heterocycloalkyl, or -L-K; or R⁶ and R⁷ takentogether form a bond; each X is independently NH, S, or O; each Y isindependently NH, S, or O; R⁸ is substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedaryl, substituted or unsubstituted alkyl-aryl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted alkyl-cycloalkyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl-heteroaryl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted alkyl-heterocycloalkyl, or -L-K; L isA_(n), wherein each A is independently NR¹, S(O)_(m), O, C(═X)Y, Y(C═X),substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heterocycloalkyl; wherein each m isindependently 0-2; n is 0-7; K is a moiety that prevents systemicabsorption; provided that at least one of R¹, R², R³ or R⁴ is -L-K; or apharmaceutically acceptable prodrug thereof.
 25. The method of claim 1,wherein the ASBTI is a compound of Formula IV:

wherein R¹ is a straight chain C₁₋₆ alkyl group; R² is a straight chainC₁₋₆ alkyl group; R³ is hydrogen or a group OR¹¹ in which R¹¹ ishydrogen, optionally substituted C₁₋₆ alkyl or a C₁₋₆ alkylcarbonylgroup; R⁴ is pyridyl or an optionally substituted phenyl; R⁵, R⁶ and R⁸are the same or different and each is selected from: hydrogen, halogen,cyano, R¹⁵-acetylide, OR¹⁵, optionally substituted C₁₋₆ alkyl, COR¹⁵,CH(OH)R¹⁵, S(O)_(n)R¹⁵, P(O)(OR¹⁵)₂, OCOR¹⁵, OCF₃, OCN, SCN, NHCN,CH₂OR¹⁵, CHO, (CH₂)_(p)CN, CONR¹²R¹³, (CH₂)_(p)CO₂R¹⁵, (CH₂)_(p)NR¹²R¹³,CO₂R¹⁵, NHCOCF₃, NHSO₂R¹⁵, OCH₂OR¹⁵, OCH═CHR¹⁵, O(CH₂CH₂O)_(n)R¹⁵,O(CH₂)_(p)SO₃R¹⁵, O(CH₂)_(p)NR¹²R¹³ and O(CH₂)_(p)N⁺R¹²R¹³R¹⁴ wherein pis an integer from 1-4, n is an integer from 0-3 and R¹², R¹³, R¹⁴ andR¹⁵ are independently selected from hydrogen and optionally substitutedC, alkyl; R⁷ is a group of the formula

wherein the hydroxyl groups may be substituted by acetyl, benzyl, or—(C₁-C₆)-alkyl-R¹⁷, wherein the alkyl group may be substituted with oneor more hydroxyl groups; R¹⁶ is —COOH, —CH₂—OH, —CH₂—O-Acetyl, —COOMe or—COOEt; R¹⁷ is H, —OH, —NH₂, —COOH or COOR¹⁸; R¹⁸ is (C₁-C₄)-alkyl or—NH—(C₁-C₄)-alkyl; X is —NH— or —O—; and R⁹ and R¹⁰ are the same ordifferent and each is hydrogen or C₁-C₆ alkyl; and salts thereof. 26.The method of claim 1, wherein the ASBTI is a compound of Formula V:

wherein: R¹ is selected from hydrogen or C₁₋₆alkyl; One of R¹ and R² areselected from hydrogen or C₁₋₆alkyl and the other is selected fromC₁₋₆alkyl; R^(x) and R^(y) are independently selected from hydrogen,hydroxy, amino, mercapto, C₁₋₆alkyl, C₁₋₆alkoxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2; R^(z) isselected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆-alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl; n is 0-5; one of R⁴ and R⁵ is a group offormula (VA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁷; X is —O—,—N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) is hydrogen orC₁₋₆alkyl and b is 0-2; Ring A is aryl or heteroaryl; wherein Ring A isoptionally substituted on carbon by one or more substituents selectedfrom R¹⁸; R⁷ is hydrogen, C₁₋₆alkyl, carbocyclyl or heterocyclyl;wherein R⁷ is optionally substituted on carbon by one or moresubstituents selected from R¹⁹; and wherein if said heterocyclylcontains an —NH— group, that nitrogen may be optionally substituted by agroup selected from R²⁰; R⁸ is hydrogen or C₁-s-alkyl; R⁹ is hydrogen orC₁₋₆alkyl; R¹⁰ is hydrogen, halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl,C₂₋₁₀alkynyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N—(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²¹—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²²—(C₁₋₁₀alkylene)-; wherein R¹⁰ isoptionally substituted on carbon by one or more substituents selectedfrom R²³; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁴; orR¹⁰ is a group of formula (VB):

wherein: R¹¹ is hydrogen or C₁₋₆-alkyl; R¹² and R¹³ are independentlyselected from hydrogen, halo, carbamoyl, sulphamoyl, C₁₋₁₀alkyl,C₂₋₁₀alkynyl, C₂₋₁₀alkynyl, C₁₋₁₀alkanoyl, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,carbocyclyl or heterocyclyl; wherein R¹² and R¹³ may be independentlyoptionally substituted on carbon by one or more substituents selectedfrom R²⁵; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁶; R¹⁴is selected from hydrogen, halo, carbamoyl, sulphamoyl,hydroxyaminocarbonyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkanoyl, N—(C₁₋₁₀alkyl)carbamoyl, N,N—(C₁₋₁₀alkyl)₂carbamoyl,C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2, N—(C₁₋₁₀alkyl)sulphamoyl,N,N—(C₁₋₁₀alkyl)₂sulphamoyl, N—(C₁₋₁₀alkyl)sulphamoylamino,N,N—(C₁₋₁₀alkyl)₂sulphamoylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²⁷—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²⁸—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁴may be optionally substituted on carbon by one or more substituentsselected from R²⁹; and wherein if said heterocyclyl contains an —NH—group, that nitrogen may be optionally substituted by a group selectedfrom R³⁰; or R¹⁴ is a group of formula (VC):

R^(1S) is hydrogen or C₁₋₆alkyl; and R¹⁶ is hydrogen or C₁₋₆alkyl;wherein R¹⁶ may be optionally substituted on carbon by one or moregroups selected from R³¹; or R¹⁵ and R¹⁶ together with the nitrogen towhich they are attached form a heterocyclyl; wherein said heterocyclylmay be optionally substituted on carbon by one or more R³⁷; and whereinif said heterocyclyl contains an —NH— group, that nitrogen may beoptionally substituted by a group selected from R³⁸; m is 1-3; whereinthe values of R⁷ may be the same or different; R¹⁷, R¹⁸, R¹⁹, R²³, R²⁵,R²⁹, R³¹ and R³⁷ are independently selected from halo, nitro, cyano,hydroxy, amino, carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl,C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N—(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R³²—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R³³—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁷,R¹⁸, R¹⁹, R²³, R²⁵, R²⁹, R³¹ and R³⁷ may be independently optionallysubstituted on carbon by one or more R³; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R³⁵; R²¹, R²², R²⁷, R²⁸, R³² or R³³are independently selected from —O—, —NR³⁶—, —S(O)—, —NR³⁶C(O)NR³⁶—,—NR³⁶C(S)NR³⁶—, —OC(O)N═C—, —NR³⁶C(O)— or —C(O)NR³⁶—; wherein R³⁶ isselected from hydrogen or C₁₋₆alkyl, and x is 0-2; p, q, r and s areindependently selected from 0-2; R³⁴ is selected from halo, hydroxy,cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl,trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy,vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy,methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl,methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl,N,N-dimethylsulphamoyl, N-methylsulphamoylamino andN,N-dimethylsulphamoylamino; R²⁰, R²⁴, R²⁶, R³⁰, R³⁵ and R³⁸ areindependently selected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl, C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl; and wherein a “heteroaryl” is a totally unsaturated,mono or bicyclic ring containing 3-12 atoms of which at least one atomis chosen from nitrogen, sulphur and oxygen, which heteroaryl may,unless otherwise specified, be carbon or nitrogen linked; wherein a“heterocyclyl” is a saturated, partially saturated or unsaturated, monoor bicyclic ring containing 3-12 atoms of which at least one atom ischosen from nitrogen, sulphur and oxygen, which heterocyclyl may, unlessotherwise specified, be carbon or nitrogen linked, wherein a —CH₂— groupcan optionally be replaced by a —C(O)— group, and a ring sulphur atommay be optionally oxidised to form an S-oxide; and wherein a“carbocyclyl” is a saturated, partially saturated or unsaturated, monoor bicyclic carbon ring that contains 3-12 atoms; wherein a —CH₂— groupcan optionally be replaced by a —C(O) group; or a pharmaceuticallyacceptable salt or in vivo hydrolysable ester or amide formed on anavailable carboxy or hydroxy group thereof.
 27. The method of claim 26,wherein the compound of Formula V is1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((R)-1-carboxy-2-methylthio-ethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxybutyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-(R)-hydroxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((R)-1-carboxy-2-methylthioethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—{(S)-1-[N—((S)-2-hydroxy-1-carboxyethyl)carbamoyl]propyl}carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxy-2-methylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—{(R)-α-carboxy4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiadiazepine;or a pharmaceutically acceptable salt thereof.
 28. The method of claim1, wherein the ASBTI is a compound of Formula VI:

wherein: R^(v) and R^(w) are independently selected from hydrogen orC₁₋₆alkyl; one of R¹ and R² is selected from hydrogen or C₁₋₆alkyl andthe other is selected from C₁₋₆alkyl; R^(x) and R^(y) are independentlyselected from hydrogen or C₁₋₆alkyl, or one of R^(x) and R^(y) ishydrogen or C₁₋₆alkyl and the other is hydroxy or C₁₋₆alkoxy; R^(z) isselected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl; n is 0-5; one of R⁴ and RS is a group offormula (VIA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy,C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁷; X is —O—,—N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) is hydrogen orC₁₋₆alkyl and b is 0-2; Ring A is aryl or heteroaryl; wherein Ring A isoptionally substituted on carbon by one or more substituents selectedfrom R¹⁸; R⁷ is hydrogen, C₁₋₆alkyl, carbocyclyl or heterocyclyl;wherein R⁷ is optionally substituted on carbon by one or moresubstituents selected from R¹⁹; and wherein if said heterocyclylcontains an —NH— group, that nitrogen may be optionally substituted by agroup selected from R²⁰; R⁸ is hydrogen or C₁₋₆alkyl; R⁹ is hydrogen orC₁₋₆alkyl; R¹⁰ is hydrogen, halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N—(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²—(C₁₋₁₀alkylene)_(q) orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²²—(C₁₋₁₀alkylene)-; wherein R¹⁰ isoptionally substituted on carbon by one or more substituents selectedfrom R²³; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁴; orR¹⁰ is a group of formula (VIB):

wherein: R¹¹ is hydrogen or C₁₋₆alkyl; R¹² and R¹³ are independentlyselected from hydrogen, halo, nitro, cyano, hydroxy, amino, carbamoyl,mercapto, sulphamoyl, C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl,C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino,N,N—(C₁₋₁₀alkyl)₂amino, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,carbocyclyl or heterocyclyl; wherein R¹² and R¹³ may be independentlyoptionally substituted on carbon by one or more substituents selectedfrom R²⁵; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R²⁶; R¹⁴is selected from hydrogen, halo, nitro, cyano, hydroxy, amino,carbamoyl, mercapto, sulphamoyl, hydroxyaminocarbonyl, C₁₋₁₀alkyl,C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl,C₁₋₁₀alkanoyloxy, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N—(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R²⁷—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R²⁸—(C₁₋₁₀alkylene)-; wherein R¹⁴ maybe optionally substituted on carbon by one or more substituents selectedfrom R²⁹; and wherein if said heterocyclyl contains an —NH— group, thatnitrogen may be optionally substituted by a group selected from R³⁰; orR¹⁴ is a group of formula (VIC):

R¹⁵ is hydrogen or C₁₋₆alkyl; R¹⁶ is hydrogen or C₁₋₆alkyl; wherein R¹⁶may be optionally substituted on carbon by one or more groups selectedfrom R³¹; n is 1-3; wherein the values of R⁷ may be the same ordifferent; R⁷, R¹⁸, R¹⁹, R²³, R²⁵, R²⁹ or R³¹ are independently selectedfrom halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto,sulphamoyl, hydroxyaminocarbonyl, amidino, C₁₋₁₀alkyl, C₂₋₁₀alkenyl,C₂₋₁₀alkynyl, C₁₋₁₀alkoxy, C₁₋₁₀alkanoyl, C₁₋₁₀alkanoyloxy,(C₁₋₁₀alkyl)₃silyl, N—(C₁₋₁₀alkyl)amino, N,N—(C₁₋₁₀alkyl)₂amino,N,N,N—(C₁₋₁₀alkyl)₃ammonio, C₁₋₁₀alkanoylamino, N—(C₁₋₁₀alkyl)carbamoyl,N,N—(C₁₋₁₀alkyl)₂carbamoyl, C₁₋₁₀alkylS(O)_(a) wherein a is 0 to 2,N—(C₁₋₁₀alkyl)sulphamoyl, N,N—(C₁₋₁₀alkyl)₂sulphamoyl,N—(C₁₋₁₀alkyl)sulphamoylamino, N,N—(C₁₋₁₀alkyl)₂sulphamoylamino,C₁₋₁₀alkoxycarbonylamino, carbocyclyl, carbocyclylC₁₋₁₀alkyl,heterocyclyl, heterocyclylC₁₋₁₀alkyl,carbocyclyl-(C₁₋₁₀alkylene)_(p)-R³²—(C₁₋₁₀alkylene)_(q)- orheterocyclyl-(C₁₋₁₀alkylene)_(r)-R³³—(C₁₋₁₀alkylene)_(s)-; wherein R¹⁷,R¹⁸, R¹⁹, R²³, R²⁵, R²⁹ r R³¹ may be independently optionallysubstituted on carbon by one or more R³; and wherein if saidheterocyclyl contains an —NH— group, that nitrogen may be optionallysubstituted by a group selected from R³⁵; R²¹, R²², R²⁷, R²⁸, R³² or R³³are independently selected from —O—, —NR³⁶—, —S(O)—, —NR³⁶C(O)NR³⁶—,—NR³⁶C(S)NR³⁶—, —OC(O)N═C—, —NR³⁶C(O)— or —C(O)NR³⁶—; wherein R³⁶ isselected from hydrogen or C₁₋₆alkyl, and x is 0-2; p, q, r and s areindependently selected from 0-2; R³⁴ is selected from halo, hydroxy,cyano, carbamoyl, ureido, amino, nitro, carbamoyl, mercapto, sulphamoyl,trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy,vinyl, allyl, ethynyl, formyl, acetyl, formamido, acetylamino, acetoxy,methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl,methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl,N,N-dimethylsulphamoyl, N-methylsulphamoylamino andN,N-dimethylsulphamoylamino; R²⁰, R²⁴, R²⁶, R³⁰ or R³⁵ are independentlyselected from C₁₋₆alkyl, C₁₋₆alkanoyl, C₁₋₆alkylsulphonyl,C₁₋₆alkoxycarbonyl, carbamoyl, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)carbamoyl, benzyl, benzyloxycarbonyl, benzoyl andphenylsulphonyl; or a pharmaceutically acceptable salt, solvate orsolvate of such a salt, or an in vivo hydrolysable ester formed on anavailable carboxy or hydroxy thereof, or an in vivo hydrolysable amideformed on an available carboxy thereof.
 29. The method of claim 28,wherein the compound of Formula VI is1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N′—((S)-1-carboxypropyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N′—((S)-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;or a pharmaceutically acceptable salt thereof.
 30. The method of claim1, wherein the composition further comprises a bile acid sequestrant orbinder.